Loading content

Dr Nicholas Harmer

Associate Professor in Biochemistry and Co-Director of Business Engagement and Innovation

5179

+44 (0)1392 725179

Living Systems Institute TO3.14

Living Systems Institute, University of Exeter, Stocker Road, Exeter, EX4 4QD

Dr Nic Harmer in the lab

Overview

Enzyme cascades and their applications

Enzymes are nature’s catalysts. They are molecules that make reactions in biology work faster. All the chemical changes needed in living systems rely on enzymes speeding up reactions at the right time. Our work seeks to understand sets of enzymes working together – a “cascade” – to drive desirable reactions. We engineer some enzymes using evolutionary methods. We then apply this understanding to practical problems. Our key examples are: the production of sugars for use in vaccines against bacteria; and chemical transformations for drug manufacture. Our work will help to deliver vaccines or drugs at scale using fewer resources and producing less waste. It will help both with overcoming antimicrobial resistance, and achieving a green future.

Time-resolved structural studies of enzymes

The key steps in enzyme catalysis occur quickly in rare events on a molecular timescale. To gain deeper understanding of how enzymes work, we want to determine the structure of enzymes as they move through the catalytic cycle. Achieving this requires the latest structural biology innovations. We aim to use our well-characterised systems from the enzyme cascade projects to work with synchrotron experts to catch enzymes in the act of catalysis and better understand how enzymes achieve their amazing speeding up of reactions.

Research Team

Courtney Lendon (PhD)

William Stuart (PhD)

Rhys Cutlan (PhD)

I am a member of the Biochemistry, Chemical Biology and Structural Biology and Microbes and Disease research groups.

Qualifications

Biography

Prof. Harmer trained for his PhD in X-ray crystallography in the laboratory of Prof. Sir Tom Blundell at the University of Cambridge. He spent three further years in Cambridge as a postdoctoral research associate working on growth factors and enzymes, and learning biophysical techniques. He then worked for AstraZeneca in Mölndal, Sweden as a structural biologist for one year to gain an understanding of industry. He joined the University of Exeter in 2007 and established a research programme on the structure and function of enzymes in biological cascades. In 2017 he was amongst the first PIs to join the Living Systems Institute.

Qualifications

2000-2004 PhD Biochemistry, University of Cambridge
1999-2000 MSci Natural Sciences, University of Cambridge
1996-2000 2003 MA Natural Sciences, University of Cambridge

Career

2018-present Associate Professor in Biochemistry, Living Systems Institute, University of Exeter, UK

2012-2018 Senior Lecturer in Structural Biochemistry, School of Biosciences, University of Exeter, UK
2007-2012 Lecturer in Structural Biochemistry, School of Biosciences, University of Exeter, UK
2006-2007 Senior Scientist, AstraZeneca R&D Molndal, Sweden
2003-2006 Research Associate, Department of Biochemistry, University of Cambridge, UK

Research group links

Dr Nic Harmer in the lab

Research

Research interests

Enzyme cascades and their applications

Our work aims to understand enzymes as biological catalysts. We seek to understand enzymes individually from a structure-function perspective: we determine the structure of enzymes and align this to function using enzyme assays and complementary methods. Our aim is to understand how enzymes achieve rate enhancement, and how this can be modulated for different functions. Where necessary, we are engineering enzymes using ancestral sequence reconstruction to obtain proteins with novel properties. Key example enzymes are carbohydrate active enzymes, carboxylic acid reductases and prolyl-peptidyl isomerases.

Alongside our studies of individual enzymes, we also aim to understand how groups of enzymes work together to achieve larger transformations. Our particular interest is in modelling groups of enzymes to see whether their individual properties explain their behaviour as a group. Building faithful models of enzyme activity is essential for process upscaling to the quantities required for production levels. We use Python, Matlab or R as appropriate to the experimental problem.

Our enzyme studies are being applied to important problems in life and molecular sciences. Current main projects for the group are the biosynthesis of the Coxiella burnetii O-antigen, and enzyme cascades based around carboxylic acid reductases. Coxiella burnetii infects sheep, goats and cattle across the world, causing abortions and stillbirths, and causes a disease called Q fever in humans. We aim to use our understanding of the O-antigen biosynthesis to help develop a vaccine (funding: BBSRC, Dstl). We are also developing enzyme cascades that can be used to synthesise chiral building blocks for drug manufacture with reduced resources and waste streams (funding: BBSRC, GSK).

Research projects

Current key projects include:

1. Coxiella burnetii O-antigen
Q fever is a disease of ruminant domestic animals, and only a few bacteria are necessary to infect humans. The pathogen is found globally, and is economically important as it can cause abortions in domestic animals. My group is investigating the biosynthesis of the O-antigen of C. burnetii. This is the only polysaccharide of this organism, and is an excellent candidate for novel vaccines. This work is undertaken in collaboration with Prof. Rick Titball (Exeter), Dr. Joann Prior (Dstl), Prof. Brendan Wren and Dr. Jon Cuccui (London School of Hygiene and Tropical Medicine), and Prof. Rob Field (John Innes Centre). This work is funded by BBSRC and Dstl.

2. Enzyme cascades for green chemistry

There is an increasing desire to replace organic chemistry methods with enzymes where possible. This reduces the use of polluting chemicals and solvents. Enzymes also offer the opportunity to generate chiral products with high purity. Using a cascade of enzymes offers further opportunities to reduce side reactions, or to minimise the concentrations of less stable intermediates. We are working on cascades based on the carboxylic acid reductases (CAR). These enzymes reduce acid to aldehydes, producing a reactive substrate for further enzymes. We have developed the most thermostable CAR available to date and aim to use this for biocatalysis at higher temperatures. This work is being undertaken in collaboration with Prof. Jenny Littlechild (Exeter) and Dr. Richard Lloyd (GSK), and is funded by GSK and BBSRC.

3. Chaperones of B. pseudomallei.
Chaperones are essential for the correct folding of many proteins in all organisms, and as such they inevitably contribute to the viability and infectivity of micro-organisms. Moreover, chaperones of the FK-506 binding protein family have been identified as significant virulence factors in a range of micro-organisms. My group is aiming to understand the contribution of chaperones to B. pseudomallei infectivity, and determine the potential for novel antimicrobials. This project is being undertaken in collaboration with Dr. Andy Scott (Dstl), Dr. Mitali Sarkar-Tyson (University of Western Australia) and Prof. Ulrike Holzgrabe (University of Würzburg), and is funded by Dstl. It has received further funding from Interreg.

Research grants:

BBSRC - Glycoengineering of Veterinary Vaccines (CoI, Exeter co-PI)

BBSRC/Dstl - Defining the O-antigen biosynthetic pathways in zoonotic Coxiella burnetii (PI)

BBSRC/GSK - Synthetic biology for green chemistry: Building in vivo enzymatic cascades using Carboxylic acid reductases (CARs) – (PI)

BBSRC/ERAnet - HotSolute - Thermophilic bacteria and archaeal chassis for extremolyte production (CoI with Jenny Littlechild)

Research networks

Current external collaborators include Dr. Joann Prior, Dr. Andy Scott (Dstl); Professor Rob Field (University of Manchester); Prof. Brendan Wren and Dr. Jon Cuccui (London School of Hygiene and Tropical Medicine); Prof. Ulrike Holzgrabe (University of Würzburg); Dr. Mitali Sarkar-Tyson (University of Western Australia); Dr. Jiayun Pang (University of Greenwich); Dr. Richard Lloyd (GSK Stevenage).

Publications

Key publications | Publications by category | Publications by year

Key publications

Louis M, Clamens T, Tahrioui A, Desriac F, Rodrigues S, Rosay T, Harmer N, Diaz S, Barreau M, Racine P-J, et al (2022). Pseudomonas aeruginosa Biofilm Dispersion by the Human Atrial Natriuretic Peptide. Adv Sci (Weinh), 9(7). Abstract. Author URL.

Cross AR, Roy S, Vivoli Vega M, Rejzek M, Nepogodiev SA, Cliff M, Salmon D, Isupov MN, Field RA, Prior JL, et al (2022). Spinning sugars in antigen biosynthesis: characterization of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases. J Biol Chem, 298(5). Abstract. Author URL.

Harmer NJ, Hill AM (2021). Unique Data Sets and Bespoke Laboratory Videos: Teaching and Assessing of Experimental Methods and Data Analysis in a Pandemic. Journal of Chemical Education, 98(12), 4094-4100.

Finnigan W, Cutlan R, Snajdrova R, Adams J, Littlechild J, Harmer NJ (2019). Engineering a Seven Enzyme Biotransformation using Mathematical Modelling and Characterized Enzyme Parts. ChemCatChem

Thomas A, Cutlan R, Finnigan W, Van Der Giezen M, Harmer N (2019). Highly thermostable carboxylic acid reductases generated by ancestral sequence reconstruction. Abstract.

Harmer NJ, Vivoli M, Pang J (2017). A half-site multimeric enzyme achieves its cooperativity without conformational changes. Scientific Reports, 7, 16529-16529.

Publications by category

Journal articles

Sheppard EC, Rogers S, Harmer NJ, Chahwan R (In Press). A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity. Abstract.

Xu Y, Smith R, Vivoli M, Ema M, Goos N, Gehrke S, Harmer NJ, Wagner GK (In Press). Covalent inhibitors of LgtC: a blueprint for the discovery of non-substrate-like inhibitors for bacterial glycosyltransferases. Bioorganic & Medicinal Chemistry

Barker S, Harding SV, Gray D, Richards MI, Atkins HS, Harmer N (In Press). Drug screening to identify compounds to act as co-therapies for the treatment of pathogenic Burkholderia. Abstract.

Cross AR, Roy S, Vega MV, Rejzek M, Nepogodiev SA, Cliff M, Salmon D, Isupov MN, Field RA, Prior JL, et al (In Press). Spinning sugars in antigen biosynthesis: a direct study of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases. Abstract.

Roy S, Vega MV, Ames JR, Britten N, Kent A, Evans K, Isupov MN, Harmer NJ (In Press). Structure and function of N-acetylglucosamine kinase illuminates the catalytic mechanism of ROK kinases. Abstract.

Scheuplein NJ, Lohr T, Vivoli Vega M, Ankrett D, Seufert F, Kirchner L, Harmer NJ, Holzgrabe U (2023). Fluorescent probe for the identification of potent inhibitors of the macrophage infectivity potentiator (Mip) protein of Burkholderia pseudomallei. SLAS Discovery

Roy S, Vivoli Vega M, Ames JR, Britten N, Kent A, Evans K, Isupov MN, Harmer NJ (2023). The ROK kinase N-acetylglucosamine kinase uses a sequential random enzyme mechanism with successive conformational changes upon each substrate binding. Journal of Biological Chemistry, 299(4), 103033-103033.

Iwasaki J, Lorimer DD, Vivoli-Vega M, Kibble EA, Peacock CS, Abendroth J, Mayclin SJ, Dranow DM, Pierce PG, Fox D, et al (2022). Broad-spectrum in vitro activity of macrophage infectivity potentiator inhibitors against Gram-negative bacteria and Leishmania major. J Antimicrob Chemother, 77(6), 1625-1634. Abstract. Author URL.

Barker S, Harding SV, Gray D, Richards MI, Atkins HS, Harmer NJ (2021). Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species. PLOS ONE, 16(3), e0248119-e0248119. Abstract.

De Rose SA, Finnigan W, Harmer NJ, Littlechild JA, consortium TH, Bettina S, Christopher B, Christina S, Benjamin M, N. IM, et al (2021). Production of the Extremolyte Cyclic 2,3-Diphosphoglycerate Using Thermus thermophilus as a Whole-Cell Factory. Frontiers in Catalysis, 1

Cutlan R, De Rose S, Isupov MN, Littlechild JA, Harmer NJ (2020). Using enzyme cascades in biocatalysis: Highlight on transaminases and carboxylic acid reductases. Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, 1868(2), 140322-140322.

Sheppard EC, Rogers S, Harmer NJ, Chahwan R (2019). A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity. Sci Rep, 9(1). Abstract. Author URL.

Harmer NJ, Roy S, Vivoli M (2019). Carbohydrate Kinases: a Conserved Mechanism Across Differing Folds. Catalysts, 9, 29-29.

Thomas A, Cutlan R, Finnigan W, van der Giezen M, Harmer N (2019). Highly thermostable carboxylic acid reductases generated by ancestral sequence reconstruction. Communications Biology, 2(1). Abstract.

Bradshaw WJ, Bruxelle J-F, Kovacs-Simon A, Harmer NJ, Janoir C, Péchiné S, Acharya KR, Michell SL (2019). Molecular features of lipoprotein CD0873: a potential vaccine against the human pathogen Clostridioides difficile. J Biol Chem, 294(43), 15850-15861. Abstract. Author URL.

Cross AR, Baldwin VM, Roy S, Essex-Lopresti AE, Prior JL, Harmer NJ (2019). Zoonoses under our noses. Microbes Infect, 21(1), 10-19. Abstract. Author URL.

Winter AJ, Williams C, Isupov MN, Crocker H, Gromova M, Marsh P, Wilkinson OJ, Dillingham MS, Harmer NJ, Titball RW, et al (2018). The molecular basis of protein toxin HicA-dependent binding of the protein antitoxin HicB to DNA. J Biol Chem, 293(50), 19429-19440. Abstract. Author URL.

Harmer NJ, Vivoli M, Pang J (2017). A half-site multimeric enzyme achieves its cooperativity without conformational changes. Scientific Reports, 7, 16529-16529.

Vivoli M, Renou J, Chevalier A, Norville IH, Diaz S, Juli C, Atkins H, Holzgrabe U, Renard P-Y, Sarkar-Tyson M, et al (2017). A miniaturized peptidyl-prolyl isomerase enzyme assay. Anal Biochem, 536, 59-68. Abstract. Author URL.

Bayliss M, Donaldson MI, Nepogodiev SA, Pergolizzi G, Scott AE, Harmer NJ, Field RA, Prior JL (2017). Structural characterisation of the capsular polysaccharide expressed by Burkholderia thailandensis strain E555:: wbiI (pKnock-KmR) and assessment of the significance of the 2-O-acetyl group in immune protection. Carbohydr Res, 452, 17-24. Abstract. Author URL.

Steinberg G, Harmer NJ, Schuster M, Kilaru S (2017). Woronin body-based sealing of septal pores. Fungal Genet Biol, 109, 53-55. Abstract. Author URL.

Finnigan W, Thomas A, Cromar H, Gough B, Snajdrova R, Adams JP, Littlechild JA, Harmer NJ (2016). Characterization of carboxylic acid reductases as enzymes in the toolbox for synthetic chemistry. ChemCatChem, in press

Seufert F, Kuhn M, Hein M, Weiwad M, Vivoli M, Norville IH, Sarkar-Tyson M, Marshall LE, Schweimer K, Bruhn H, et al (2016). Development, synthesis and structure-activity-relationships of inhibitors of the macrophage infectivity potentiator (Mip) proteins of Legionella pneumophila and Burkholderia pseudomallei. Bioorg Med Chem, 24(21), 5134-5147. Abstract. Author URL.

N'Diaye A, Mijouin L, Hillion M, Diaz S, Konto-Ghiorghi Y, Percoco G, Chevalier S, Lefeuvre L, Harmer NJ, Lesouhaitier O, et al (2016). Effect of Substance P in Staphylococcus aureus and Staphylococcus epidermidis Virulence: Implication for Skin Homeostasis. FRONTIERS IN MICROBIOLOGY, 7 Author URL.

Harmer NJ, Chahwan R (2016). Isotype switching: Mouse IgG3 constant region drives increased affinity for polysaccharide antigens. Virulence, 7(6), 623-626. Author URL.

sayer C, Finnigan W, Isupov MN, Levisson M, Kengen SWM, van der Oost J, Harmer NJ, Littlechild JA (2016). Structural and biochemical characterisation of Archaeoglobus fulgidus esterase reveals a bound CoA molecule in the vicinity of the active site. Scientific Reports, 6, 25542-25542. Abstract.

Blaszczyk M, Harmer NJ, Chirgadze DY, Ascher DB, Blundell TL (2015). Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors. Progress in Biophysics and Molecular Biology, 118(3), 103-111. Abstract.

Blaszczyk M, Harmer NJ, Chirgadze DY, Ascher DB, Blundell TL (2015). Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors. Prog Biophys Mol Biol, 118(3), 103-111. Abstract. Author URL.

Rosay T, Bazire A, Diaz S, Clamens T, Blier A-S, Mijouin L, Hoffmann B, Sergent J-A, Bouffartigues E, Boireau W, et al (2015). Pseudomonas aeruginosa Expresses a Functional Human Natriuretic Peptide Receptor Ortholog: Involvement in Biofilm Formation. mBio, 6(4).

UNLABELLED: Considerable evidence exists that bacteria detect eukaryotic communication molecules and modify their virulence accordingly. In previous studies, it has been demonstrated that the increasingly antibiotic-resistant pathogen Pseudomonas aeruginosa can detect the human hormones brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) at micromolar concentrations. In response, the bacterium modifies its behavior to adapt to the host physiology, increasing its overall virulence. The possibility of identifying the bacterial sensor for these hormones and interfering with this sensing mechanism offers an exciting opportunity to directly affect the infection process. Here, we show that BNP and CNP strongly decrease P. aeruginosa biofilm formation. Isatin, an antagonist of human natriuretic peptide receptors (NPR), prevents this effect. Furthermore, the human NPR-C receptor agonist cANF(4-23) mimics the effects of natriuretic peptides on P. aeruginosa, while sANP, the NPR-A receptor agonist, appears to be weakly active. We show in silico that NPR-C, a preferential CNP receptor, and the P. aeruginosa protein AmiC have similar three-dimensional (3D) structures and that both CNP and isatin bind to AmiC. We demonstrate that CNP acts as an AmiC agonist, enhancing the expression of the ami operon in P. aeruginosa. Binding of CNP and NPR-C agonists to AmiC was confirmed by microscale thermophoresis. Finally, using an amiC mutant strain, we demonstrated that AmiC is essential for CNP effects on biofilm formation. In conclusion, the AmiC bacterial sensor possesses structural and pharmacological profiles similar to those of the human NPR-C receptor and appears to be a bacterial receptor for human hormones that enables P. aeruginosa to modulate biofilm expression. IMPORTANCE: the bacterium Pseudomonas aeruginosa is a highly dangerous opportunist pathogen for immunocompromised hosts, especially cystic fibrosis patients. The sites of P. aeruginosa infection are varied, with predominance in the human lung, in which bacteria are in contact with host molecular messengers such as hormones. The C-type natriuretic peptide (CNP), a hormone produced by lung cells, has been described as a bacterial virulence enhancer. In this study, we showed that the CNP hormone counteracts P. aeruginosa biofilm formation and we identified the bacterial protein AmiC as the sensor involved in the CNP effects. We showed that AmiC could bind specifically CNP. These results show for the first time that a human hormone could be sensed by bacteria through a specific protein, which is an ortholog of the human receptor NPR-C. The bacterium would be able to modify its lifestyle by favoring virulence factor production while reducing biofilm formation.

Abstract. Author URL.

Vivoli M, Isupov MN, Nicholas R, Hill A, Scott AE, Kosma P, Prior JL, Harmer NJ (2015). Unraveling the B. pseudomallei Heptokinase WcbL: from Structure to Drug Discovery. Chemistry and Biology, 22(12), 1622-1632. Abstract.

Begley DW, Fox D, Jenner D, Juli C, Pierce PG, Abendroth J, Muruthi M, Safford K, Anderson V, Atkins K, et al (2014). A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins. Antimicrobial Agents and Chemotherapy, 58(3), 1458-1467. Abstract.

Vivoli M, Novak HR, Littlechild JA, Harmer NJ (2014). Determination of Protein-ligand Interactions Using Differential Scanning Fluorimetry. Journal of Visualized Experiments(91).

Vivoli M, Novak HR, Littlechild JA, Harmer NJ (2014). Determination of protein-ligand interactions using differential scanning fluorimetry. J Vis Exp(91). Abstract. Author URL.

Vivoli M, Ayres E, Beaumont E, Isupov MN, Harmer NJ (2014). Structural insights into WcbI, a novel polysaccharide-biosynthesis enzyme. IUCrJ, 1, 28-38.

Butt A, Higman VA, Williams C, Crump MP, Hemsley CM, Harmer N, Titball RW (2014). The HicA toxin from Burkholderia pseudomallei has a role in persister cell formation. Biochem J, 459(2), 333-344. Abstract. Author URL.

Butt A, Harmer N, Müller C, Titball RW (2013). Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei. FEMS Microbiol Lett, 338(1), 86-94. Abstract.

Cuccui J, Milne TS, Harmer N, George AJ, Harding SV, Dean RE, Scott AE, Sarkar-Tyson M, Wren BW, Titball RW, et al (2012). Characterization of the Burkholderia pseudomallei K96243 capsular polysaccharide I coding region. Infection and Immunity, 80, 1209-1221. Abstract. Author URL.

Schuster M, Treitschke S, Kilaru S, Molloy J, Harmer NJ, Steinberg G (2012). Myosin-5, kinesin-1 and myosin-17 cooperate in secretion of fungal chitin synthase. EMBO J, 31(1), 214-227. Abstract. Author URL.

Norville IH, Harmer NJ, Harding SV, Fischer G, Keith KE, Brown KA, Sarkar-Tyson M, Titball RW (2011). A Burkholderia pseudomallei macrophage infectivity potentiator-like protein has rapamycin-inhibitable peptidylprolyl isomerase activity and pleiotropic effects on virulence. Infect Immun, 79(11), 4299-4307. Abstract. Author URL.

Norville IH, Breitbach K, Eske-Pogodda K, Harmer NJ, Sarkar-Tyson M, Titball RW, Steinmetz I (2011). A novel FK-506-binding-like protein that lacks peptidyl-prolyl isomerase activity is involved in intracellular infection and in vivo virulence of Burkholderia pseudomallei. Microbiology (Reading), 157(Pt 9), 2629-2638. Abstract. Author URL.

Thomas RM, Twine SM, Fulton KM, Tessier L, Kilmury SLN, Ding W, Harmer N, Michell SL, Oyston PCF, Titbal RW, et al (2011). Glycosylation of DsbA in Francisella tularensis subsp. Tularensis. Journal of Bacteriology, 193(19), 5498-5509. Abstract.

Norville I, O'Shea K, Sarkar-Tyson M, Zheng S, Titball RW, Varani G, Harmer NJ (2011). The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development. Biochemical Journal, 437, 413-422. Abstract.

Norville IH, O'Shea K, Sarkar-Tyson M, Zheng S, Titball RW, Varani G, Harmer NJ (2011). The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development. Biochem J, 437(3), 413-422. Abstract. Author URL.

Harmer NJ (2010). The Structure of Sedoheptulose-7-Phosphate Isomerase from Burkholderia pseudomallei Reveals a Zinc Binding Site at the Heart of the Active Site. JOURNAL OF MOLECULAR BIOLOGY, 400(3), 379-392. Author URL.

Goodger SJ, Robinson CJ, Murphy KJ, Gasiunas N, Harmer NJ, Blundell TL, Pye DA, Gallagher JT (2008). Evidence that heparin saccharides promote FGF2 mitogeneisis through two distinct mechanisms. Journal of Biological Chemistry, 283, 13001-13008.

Harmer NJ, King, J.D. Palmer, C.M. Preston, A. Maskell DJ, Blundell TL (2007). Cloning, expression, purification and preliminary crystallographic analysis of the short-chain dehydrogenase enzymes WbmF, WbmG and WbmH from Bordetella bronchiseptica. Acta Crystallographica F, 63(8), 711-715.

King JD, Harmer NJ, Preston A, Palmer CM, Rejzek M, Field RA, Blundell TL, Maskell DJ (2007). Predicting protein function from structure - the roles of short chain dehydrogenase / reductase enzymes in bordetella O-antigen biosynthesis. Journal of Molecular Biology, 374, 749-763.

Harmer NJ (2007). The fibroblast growth factor (FGF) - FGF receptor complex: Progress towards the physiological state. Topics in Current Chemistry, 272, 83-116. Abstract.

Ryu EK, Cho, K.J. Kim, J.K. Harmer NJ, Blundell TL, Kim, K.H. (2006). Expression and purification of recombinant human fibroblast growth factor receptor in E. coli. Protein Expression and Purification, 49, 15-22.

Harmer NJ (2006). Insights into the role of heparan sulphate in fibroblast growth factor signalling. Biochemical Society Transactions, 34(3), 442-445.

Harmer NJ, Robinson CJ, Adam LE, Ilag LL, Robinson CV, Gallagher JT, Blundell TL (2006). Multimers of the fibroblast growth factor (FGF)-FGF receptor-saccharide complex are formed on long oligers of heparin. Biochemical Journal, 393(3), 741-748.

Blundell TL, Sibanda BL, Montalvao RW, Brewerton S, Chelliah V, Harmer NJ, Worth CL, Davies O, Burke D (2006). Structural biology and bioinformatics in drug design: opportunities and challenges for target identification and lead discovery. Philosophical Transactions of the Royal Society B: Biological Sciences, 361(1467), 413-423.

Harmer NJ, Sivac JM, Amaya E, Blundell TL (2005). 1.15 angstrom crystal structure of the X-tropicalis Spred 1 EVH1 domain suggests a fourth distinct peptide-binding mechanism within the EVH1 family. FEBS Letters, 579(5), 1161-1166.

Robinson CJ, Harmer, N.J. Goodger, S.J. Blundell, T.L. Gallagher JT (2005). Cooperative dimerization of FGF1 upon a single heparin saccharide may drive the formation of 2:2:1 FGF-FGFR-heparin ternary complexes. Journal of Biological Chemistry, 280, 42274-42282.

Harmer NJ, Pellegrini L, Chirgadze D, Fernandez-Recio J, Blundell TL (2004). The crystal structure of fibroblast growth factor (FGF) 19 reveals novel features of the FGF family and offers a structural basis for its unusual receptor affinity. Biochemistry, 43(3), 629-640.

Harmer NJ, Ilag LL, Mulloy B, Pellegrini L, Robinson CV, Blundell TL (2004). Towards a resolution of the stoichiometry of the fibroblast growth factor (FGF) - FGF receptor-Heparin complex. Journal of Molecular Biology, 339(4), 821-834.

Harmer NJ, Chirgadze D, Kim KH, Pellegrini L, Blundell TL (2003). The structural biology of growth factor receptor activation. Biophysical Chemistry, 100, 545-553.

Schuh AC, Watkins, N.A. Nguyen, Q. Harmer, N.J. Lin M, Prosper JY, Campbell K, Sutherland DR, Metcalfe P, Horsfeld W, et al (2002). A tyrosine703serine polymorphism of CD109 defines the Gov platelet alloantigens. Blood, 99, 1692-1698.

Blundell TL, Bolanos-Garcia V, Chirgadze DY, Harmer NJ, Lo T, Pellegrini L, Sibanda BL (2002). Asymmetry in the multiprotein systems of molecular biology. Structural Chemistry, 13(3-4), 405-412. Abstract.

Ouwehand WH, Watkins NA, Nguyen Q, Harmer NJ, Lin M, Prosper JYA, Campbell K, Sutherland DR, Metcalfe P, Horsfall W, et al (2001). A Tyrosine(703) serine polymorphism of CD109 defines the Gov platelet alloantigens. BLOOD, 98(11), 443A-443A. Author URL.

Nagendra HG, Harrington, A.E. Harmer, N.J. Pellegrini, L. Blundell TL, Burke DF (2001). Sequence analyses and comparative modeling of fly and worm fibroblast growth factor receptors indicate that the determinants for FGF and heparin binding are retained in evolution. FEBS Letters, 501, 51-58.

Chapters

Blundell TL, Bolanos-Garcia V, Chirgadze DY, Harmer NJ, Lo T, Pellegrini L, Lynn Sibanda B (2015). Asymmetry in the multiprotein systems of molecular biology. In (Ed) Science of Crystal Structures: Highlights in Crystallography, 231-237. Abstract.

Harmer NJ (2005). Chapter 14 Role of Heparan Sulfate in Fibroblast Growth Factor Signaling. In (Ed) Chemistry and Biology of Heparin and Heparan Sulfate, 399-434.

Harmer, N.J. (2005). Role of heparan sulfate in fibroblast growth factor signaling. In Garg H, Linhardt R, Hales C (Eds.) Chemistry and Biology of Heparin and Heparan Sulfate, New York: Elsevier.

Conferences

Harmer NJ, Norville I, Zheng S, O'Shea K, Sarkar-Tyson M, Titball RW, Varani G (2011). THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET. Society for General Microbiology Spring Conference. 11th - 14th Apr 2011. Abstract.

Norville I, Zheng S, O'Shea K, Sarkar-Tyson M, Titball RW, Varani G, Harmer NJ (2011). THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET. SWSBC 2011. 11th - 12th Jul 2011. Abstract.

Harmer NJ (2010). Structure and function of sedoheptulose-7-phosphate isomerase from Burkholderia pseudomallei, an unusual metalloenzyme. Enzymes, Cofactors and Metabolic pathways. 18th - 23rd Jul 2010. Abstract.

Harmer NJ, Norville I, Zheng S, O'Shea K, Sarkar-Tyson M, Titball RW, Varani G (2010). THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET. Melioidosis 2010. 30th Nov - 3rd Dec 2010. Abstract.

Robinson CJ, Harmer NJ, Blundell TL, Gallagher JT (2004). Studying the role of heparin in the formation of FGF1-FGFR2 complexes using gel chromatography. Author URL.

Publications by year

In Press

Sheppard EC, Rogers S, Harmer NJ, Chahwan R (In Press). A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity. Abstract.

Thomas A, Evans BD, van der Giezen M, Harmer NJ (In Press). Survivor bias drives overestimation of stability in reconstructed ancestral proteins. Abstract.

2023

Cross A, Roy S, Vivoli Vega M, Rejzek M, Nepogodiev S, Cliff M, Salmon D, Isupov M, Field R, Prior J, et al (2023). Spinning sugars in antigen biosynthesis: a direct study of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases - dataset.

Seetaloo N (2023). Synuclein plasticity: the Achilles’ heel of nerve function linked to the onset of Parkinson’s disease.

Lewy bodies – the hallmarks of Parkinson’s disease – are majorly constituted of aggregates of the presynaptic protein alpha-synuclein. The molecular mechanism of alpha-synuclein aggregation through which it changes dramatically from a soluble disordered monomer to insoluble structured fibrils remains unknown. As an intrinsically disordered protein, alpha-synuclein does not have a specific three-dimensional structure, but rather behaves mostly as a meta-stable ensemble of highly dynamic conformers, and as such undergoes rapid kinetics, making it almost impossible to measure its conformational changes with most techniques. Millisecond amide hydrogen exchange can provide valuable insights on the dynamic behaviour of proteins, especially at flexible regions. Thus, the work in this thesis reports on the development of methods and tools for hydrogen/deuterium-exchange mass spectrometry (HDX-MS) and the application of these for the study of aSyn under physiological conditions. In the first part of this thesis, high resolution on the alpha-synuclein monomer was achieved over two dimensions: time and space. Using a novel in-house rapid- mixing quench-flow instrument, hydrogen/deuterium-exchange mass spectrometry data on alpha-synuclein on the millisecond timescale was attained. Furthermore, using a ‘soft’ gas-phase mass spectrometry fragmentation technique called Electron Transfer Dissociation, structural resolution in the protein increased. The second part of this work focuses on the development of a software, HDfleX, in an effort to primarily automate the HDX-MS workflow and allow the merging of HDX-MS data at different levels: bottom-up, middle-down and top-down. The rest of the thesis uses the tools and methods developed earlier on to explore the effects of different solution conditions (cellular compartments and salt cations) on the monomeric conformations of aSyn, and how these correlate to the different stages of aggregation and the ensuing fibril polymorphs. Altogether, the achievements in this work will allow us to better understand the plasticity of the alpha-synuclein monomer as it cycles through different local environments.

Abstract.

2022

Cutlan R (2022). Synthetic Biology for Green Chemistry: Building in Vivo Enzymatic Cascades Using Carboxylic Acid Reductases (CARs).

Biocatalysis has a proven track record of offering replacements for individual chemical reactions with a lower environmental impact. Cascade reactions are an extension of biocatalysis; coupling a series of reactions to provide replacement for more than one chemical step. Herein, this thesis describes the engineering of a multi-enzyme cascade reaction for the production of phenylacetylcarbinol (PAC). Using a carboxylic acid reductase (CAR) from Mycobacterium phlei and a pyruvate decarboxylase from Acetobacter pasteurianus this thesis demonstrated a biocatalytic cascade reaction in which benzoic acid and pyruvate are converted into PAC. This cascade was combined with several other enzymes to recycle spent cofactors and deplete inhibitor by-products.
Furthermore, this thesis has highlighted the discovery of five putative enzymes; three ancestral CARs (AncCARs) and two thiamine diphosphate (ThDP) dependent enzymes. CARs typically have poor stability and thus limited tractability in industrial reactions. Within this study ancestral sequence reconstruction was performed on type I CARs. This is a developing engineering tool that can identify stabilizing and enzymatically neutral mutations throughout a protein. A combined algorithm approach was used to reconstruct functional ancestors of the Mycobacterial and Nocardial Type I CAR orthologues. Carboxylic acid reduction by Ancestral CARs was confirmed. Each showed a preference for aromatic carboxylic acids. AncCARs also showed improved tolerance to solvents, pH and in vivo-like salt-like conditions. Compared to well-studied extant CARs, AncCARs had a Tm up to 35 °C higher. Two ThDP enzymes were discovered using metagenomics. These were assessed in silico through homology modelling and docking simulations. Furthermore, this study has demonstrated the importance of each tool in the discovery of new enzymes from within the ThDP family. Our homology models were used in docking simulations with unique carboligation-like intermediates allowing a rationalization of the reactions and stereoisomerism of the products. Two functional enzymes ThDP enzymes were identified that are capable of producing PAC; one from Thermus thermophilus and another from bacterium HR16.

Abstract.

2021

De Rose SA, Harmer N, Littlechild J (2021). Production of the extremolyte cyclic 2,3-diphosphoglycerate using Thermus thermophilus as a whole-cell factory. Abstract.

De Rose S, Harmer N, Littlechild J, Finnigan W (2021). Production of the extremolyte cyclic 2,3-diphosphoglycerate using Thermus thermophilus as a whole-cell factory- DATASET.

Roy S, Vivoli Vega M, Ames J, Britten N, Kent A, Evans K, Isupov M, Harmer N (2021). Structure and function of N-acetylglucosamine kinase illuminates the catalytic mechanism of ROK kinases - experimental data.

2020

Bayliss M, Donaldson MI, Pergolizzi G, Scott AE, Nepogodiev SA, Beales L, Whelan M, Rosenberg W, Peyret H, Lomonossoff GP, et al (2020). Assessments of hepatitis B virus-like particles and Crm197 as carrier proteins in melioidosis glycoconjugate vaccines.

Cross A (2020). Defining the O-antigen biosynthetic pathways in zoonotic Coxiella burnetii: Studies of dTDP-sugar biosynthesis and LPS extraction.

Coxiella burnetii, the causative agent of Q fever, is a versatile, highly infectious select agent. Due to the immunogenic nature of its LPS-linked O-antigen, and this conveying the main determinant of virulence, a synthetic biology approach is being applied to study this molecule, with a view towards glycoconjugate vaccine design.
This thesis presents a dual approach to study of the C. burnetii O-antigen: direct characterisation of O-antigen biosynthetic enzymes, and the design of a phenol-free method by which to extract LPS material. For the former, studies focussed on characterisation of CBU_1838 as a dTDP-sugar isomerase proposed to be involved in the biosynthesis of DHHS, an O-antigen component, and a sugar unique to Coxiella. Characterisation through spectrophotometric assays, analysis of solvent exchange, and structural studies were run in parallel with another uncharacterised dTDP-sugar isomerase, StrM from Streptomyces griseus. From both kinetic assays coupled to the E. coli rhamnose-biosynthetic enzymes, and studies of solvent exchange, it is shown here that both of these query dTDP-sugar isomerases catalyse double-epimerisation of dTDP-4-keto-6-deoxy-glucose at positions 3″ and 5″. Additionally, structural studies of CBU_1838 revealed a single amino acid difference in the active site, compared to a panel of reference dTDP-sugar isomerases. From analysis of dTDP binding, and the docking of substrate-analogs, it is clear that this single residue could allow stabilisation of the hypothesised true substrate of CBU_1838, dTDP-4-keto-6-hydroxy-glucose.
Surreptitiously, preparative experiments for studies of dTDP-sugar isomerase-catalysed solvent exchange led to a novel discovery about the dTDP-glucose 4,6-dehydratase, RmlB: whilst the overall reaction is irreversible, enzyme-mediated solvent exchange at position C5″ occurs when EcRmlB is incubated with its product, dTDP-4-keto-6-deoxy-glucose.
The second approach taken to O-antigen studies, a novel method for LPS extraction, unfortunately did not yield tangible results. However, methods for growth of the Nine Mile II strain of C. burnetii were optimised, and areas for extraction improvement have been highlighted.

Abstract.

Harmer N, Barker S, Harding S, Gray D, Richards M, Atkins H (2020). Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species - underpinning data.

2019

Sheppard EC, Rogers S, Harmer NJ, Chahwan R (2019). A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity. Sci Rep, 9(1). Abstract. Author URL.

Thomas A (2019). Ancestral sequence reconstruction as an accessible tool for the engineering of biocatalyst stability.

Synthetic biology is the engineering of life to imbue non-natural functionality. As such, synthetic biology has considerable commercial potential, where synthetic metabolic pathways are utilised to convert low value substrates into high value products. High temperature biocatalysis offers several system-level benefits to synthetic biology, including increased dilution of substrate, increased reaction rates and decreased contamination risk. However, the current gamut of tools available for the engineering of thermostable proteins are either expensive, unreliable, or poorly understood, meaning their adoption into synthetic biology workflows is treacherous. This thesis focuses on the development of an accessible tool for the engineering of protein thermostability, based on the evolutionary biology tool ancestral sequence reconstruction (ASR). ASR allows researchers to walk back in time along the branches of a phylogeny and predict the most likely representation of a protein family’s ancestral state. It also has simple input requirements, and its output proteins are often observed to be thermostable, making ASR tractable to protein engineering.

Chapter 2 explores the applicability of multiple ASR methods to the engineering of a carboxylic acid reductase (CAR) biocatalyst. Despite the family emerging only 500 million years ago, ancestors presented considerable improvements in thermostability over their modern counterparts. We proceed to thoroughly characterise the ancestral enzymes for their inclusion into the CAR biocatalytic toolbox.

Chapter 3 explores why ASR derived proteins may be thermostable despite a mesophilic history. An in silico toolbox for tracking models of protein stability over simulated evolutionary time at the sequence, protein and population level is built. We provide considerable evidence that the sequence alignments of simulated protein families that evolved at marginal stability are saturated with stabilising residues. ASR therefore derives sequences from a dataset biased toward stabilisation.

Importantly, while ASR is accessible, it still requires a steep learning curve based on its requirements of phylogenetic expertise. In chapter 4, we utilise the evolutionary model produced in chapter 3 to develop a highly simplified and accessible ASR protocol. This protocol was then applied to engineer CAR enzymes that displayed dramatic increases in thermostability compared to both modern CARs and the thermostable AncCARs presented in chapter 2.

Abstract.

Harmer NJ, Roy S, Vivoli M (2019). Carbohydrate Kinases: a Conserved Mechanism Across Differing Folds. Catalysts, 9, 29-29.

finnigan W, Cutlan R, Snajdrova R, Adams J, Littlechild J, Harmer NJ (2019). Engineering a Seven Enzyme Biotransformation using Mathematical Modelling and Characterized Enzyme Parts (dataset).

Finnigan W, Cutlan R, Snajdrova R, Adams JP, Littlechild JA, Harmer NJ (2019). Engineering a seven enzyme biotransformation using mathematical modelling and characterized enzyme parts.

Thomas A, Cutlan R, Finnigan W, Van Der Giezen M, Harmer N (2019). Highly thermostable carboxylic acid reductases generated by ancestral sequence reconstruction. Abstract.

Sheppard E (2019). Nucleases and histone acetyltransferases in DNA repair and immune diversity.

DNA repair mechanisms are essential for genome maintenance and adaptive immunity. A careful balance must be achieved whereby highly accurate and efficient canonical repair protects the genome from accumulating mutations that lead to aging and cancer, and yet mutation and error-prone non-canonical repair is required for generating immune diversity.

Immune diversity is achieved within a tightly regulated environment in which mutator proteins are directed to the antibody locus to introduce a swathe of DNA damage. This produces high affinity antibodies that recognise an infinite number of invading pathogens. This process of secondary antibody diversification is dependent on both active transcription and DNA repair.

Downstream of histone signalling, DNA repair nucleases are recruited to remove the damaged bases. The structure of damaged regions in the DNA can have very different conformations depending on whether the source of the damage is endogenous or exogenous. Specific DNA nucleases recognise particular DNA substrates and generate DNA intermediates that are repaired in conjunction with polymerases and ligases.

Despite their multitude and importance to DNA repair, very few nucleases have been characterised, while the activities of some studied nucleases remain controversial. Conventional techniques for studying DNA nucleases have several disadvantages; they are hazardous, laborious, time-consuming, and capture nuclease activity in a discontinuous manner. Recognising a need for a safer, faster alternative, a fluorescence-based method has been developed for the study of DNA nucleases, nickases and polymerases.

Key histone modifications that are known to orchestrate canonical DNA repair have since been discovered to regulate non-canonical repair at the antibody locus. The Kat5 histone lysine acetyltransferase functions highly upstream of DNA repair and promotes active transcription, yet a role for Kat5 in secondary antibody diversification has not yet been established. Using chemical inhibitors to prevent the catalytic activities of Kat5, and the genetic method of an inducible degron system for rapid and reversible downregulation of Kat5, a role for Kat5 in secondary antibody diversification is recognised, and the research contributes to our current understanding of the DNA repair signal transduction pathway.

Abstract.

Cross AR, Baldwin VM, Roy S, Essex-Lopresti AE, Prior JL, Harmer NJ (2019). Zoonoses under our noses. Microbes Infect, 21(1), 10-19. Abstract. Author URL.

2018

2017

Harmer NJ, Vivoli M, Pang J (2017). A half-site multimeric enzyme achieves its cooperativity without conformational changes. Scientific Reports, 7, 16529-16529.

Steinberg G, Harmer NJ, Schuster M, Kilaru S (2017). Woronin body-based sealing of septal pores. Fungal Genet Biol, 109, 53-55. Abstract. Author URL.

2016

Harmer NJ, Chahwan R (2016). Isotype switching: Mouse IgG3 constant region drives increased affinity for polysaccharide antigens. Virulence, 7(6), 623-626. Author URL.

2015

Blaszczyk M, Harmer NJ, Chirgadze DY, Ascher DB, Blundell TL (2015). Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors. Prog Biophys Mol Biol, 118(3), 103-111. Abstract. Author URL.

Abstract. Author URL.

2014

Vivoli M, Novak HR, Littlechild JA, Harmer NJ (2014). Determination of Protein-ligand Interactions Using Differential Scanning Fluorimetry. Journal of Visualized Experiments(91).

Vivoli M, Novak HR, Littlechild JA, Harmer NJ (2014). Determination of protein-ligand interactions using differential scanning fluorimetry. J Vis Exp(91). Abstract. Author URL.

Vivoli M, Ayres E, Beaumont E, Isupov MN, Harmer NJ (2014). Structural insights into WcbI, a novel polysaccharide-biosynthesis enzyme. IUCrJ, 1, 28-38.

2013

Butt A, Harmer N, Müller C, Titball RW (2013). Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei. FEMS Microbiol Lett, 338(1), 86-94. Abstract.

2012

2011

2010

2008

2007

Harmer NJ (2007). The fibroblast growth factor (FGF) - FGF receptor complex: Progress towards the physiological state. Topics in Current Chemistry, 272, 83-116. Abstract.

2006

Harmer NJ (2006). Insights into the role of heparan sulphate in fibroblast growth factor signalling. Biochemical Society Transactions, 34(3), 442-445.

2005

Harmer NJ (2005). Chapter 14 Role of Heparan Sulfate in Fibroblast Growth Factor Signaling. In (Ed) Chemistry and Biology of Heparin and Heparan Sulfate, 399-434.

2004

Robinson CJ, Harmer NJ, Blundell TL, Gallagher JT (2004). Studying the role of heparin in the formation of FGF1-FGFR2 complexes using gel chromatography. Author URL.

2003

Harmer NJ, Chirgadze D, Kim KH, Pellegrini L, Blundell TL (2003). The structural biology of growth factor receptor activation. Biophysical Chemistry, 100, 545-553.

2002

2001

nic_harmer Details from cache as at 2023-06-07 06:02:45

Refresh publications

External Engagement and Impact

Committee/panel activities

Research Council Committees

BBSRC Panel D Core Member (since 2015)
BBSRC Pool of Experts (2014-2015)

Dr Nic Harmer in the lab

Teaching

I currently teach Year 2 Analytical Techniques in Biochemistry (BIO2090) and Metabolism (BIO2086), and Year 3 Horizons of Biochemical Research (BIO3085).

Modules

2022/23

BIO2086 - Metabolism

Supervision / Group

Postdoctoral researchers

Mirella Vivoli

Postgraduate researchers

Courtney Lendon
William Stuart

Alumni

Victoria Baldwin
Marc Bayliss
Alice Cross
Rhys Cutlan
Will Finnegan
Tara Macey
Sumita Roy
Adam Thomas

Back | Edit Profile

Profile

Dr Nicholas Harmer

Associate Professor in Biochemistry and Co-Director of Business Engagement and Innovation

Overview

Qualifications

Career

Research group links

Research

Research interests

Research projects

Research grants:

Research networks

Links

Publications

Key publications

Abstract:Pseudomonas aeruginosa Biofilm Dispersion by the Human Atrial Natriuretic Peptide.

Abstract:Spinning sugars in antigen biosynthesis: characterization of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases.

Abstract:Highly thermostable carboxylic acid reductases generated by ancestral sequence reconstruction

Publications by category

Journal articles

Abstract:A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity

Abstract:Drug screening to identify compounds to act as co-therapies for the treatment of pathogenic Burkholderia

Abstract:Spinning sugars in antigen biosynthesis: a direct study of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases

Abstract:Structure and function of N-acetylglucosamine kinase illuminates the catalytic mechanism of ROK kinases

Abstract:Broad-spectrum in vitro activity of macrophage infectivity potentiator inhibitors against Gram-negative bacteria and Leishmania major.

Abstract:Pseudomonas aeruginosa Biofilm Dispersion by the Human Atrial Natriuretic Peptide.

Abstract:Spinning sugars in antigen biosynthesis: characterization of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases.

Abstract:Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species

Abstract:A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity.

Abstract:Highly thermostable carboxylic acid reductases generated by ancestral sequence reconstruction

Abstract:Molecular features of lipoprotein CD0873: a potential vaccine against the human pathogen Clostridioides difficile.

Abstract:Zoonoses under our noses.

Abstract:The molecular basis of protein toxin HicA-dependent binding of the protein antitoxin HicB to DNA.

Abstract:A miniaturized peptidyl-prolyl isomerase enzyme assay.

Abstract:Structural characterisation of the capsular polysaccharide expressed by Burkholderia thailandensis strain E555:: wbiI (pKnock-KmR) and assessment of the significance of the 2-O-acetyl group in immune protection.

Abstract:Woronin body-based sealing of septal pores.

Abstract:Development, synthesis and structure-activity-relationships of inhibitors of the macrophage infectivity potentiator (Mip) proteins of Legionella pneumophila and Burkholderia pseudomallei.

Abstract:Structural and biochemical characterisation of Archaeoglobus fulgidus esterase reveals a bound CoA molecule in the vicinity of the active site

Abstract:Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors

Abstract:Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors.

Abstract:Pseudomonas aeruginosa Expresses a Functional Human Natriuretic Peptide Receptor Ortholog: Involvement in Biofilm Formation.

Abstract:Unraveling the B. pseudomallei Heptokinase WcbL: from Structure to Drug Discovery

Abstract:A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins

Abstract:Determination of protein-ligand interactions using differential scanning fluorimetry.

Abstract:The HicA toxin from Burkholderia pseudomallei has a role in persister cell formation.

Abstract:Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei

Abstract:Characterization of the Burkholderia pseudomallei K96243 capsular polysaccharide I coding region

Abstract:Myosin-5, kinesin-1 and myosin-17 cooperate in secretion of fungal chitin synthase.

Abstract:A Burkholderia pseudomallei macrophage infectivity potentiator-like protein has rapamycin-inhibitable peptidylprolyl isomerase activity and pleiotropic effects on virulence.

Abstract:A novel FK-506-binding-like protein that lacks peptidyl-prolyl isomerase activity is involved in intracellular infection and in vivo virulence of Burkholderia pseudomallei.

Abstract:Glycosylation of DsbA in Francisella tularensis subsp. Tularensis

Abstract:The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development

Abstract:The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development.

Abstract:The fibroblast growth factor (FGF) - FGF receptor complex: Progress towards the physiological state

Abstract:Asymmetry in the multiprotein systems of molecular biology

Chapters

Abstract:Asymmetry in the multiprotein systems of molecular biology

Conferences

Abstract:THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET

Abstract:THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET

Abstract:Structure and function of sedoheptulose-7-phosphate isomerase from Burkholderia pseudomallei, an unusual metalloenzyme

Abstract:THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET

Publications by year

In Press

Abstract:A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity

Abstract:Drug screening to identify compounds to act as co-therapies for the treatment of pathogenic Burkholderia

Abstract:Spinning sugars in antigen biosynthesis: a direct study of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases

Abstract:Structure and function of N-acetylglucosamine kinase illuminates the catalytic mechanism of ROK kinases

Abstract:Survivor bias drives overestimation of stability in reconstructed ancestral proteins

2023

Abstract:Synuclein plasticity: the Achilles’ heel of nerve function linked to the onset of Parkinson’s disease

2022

Abstract:Broad-spectrum in vitro activity of macrophage infectivity potentiator inhibitors against Gram-negative bacteria and Leishmania major.

Abstract:Pseudomonas aeruginosa Biofilm Dispersion by the Human Atrial Natriuretic Peptide.

Abstract:Spinning sugars in antigen biosynthesis: characterization of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases.

Abstract:Synthetic Biology for Green Chemistry: Building in Vivo Enzymatic Cascades Using Carboxylic Acid Reductases (CARs)

2021

Abstract:Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species

Abstract:Production of the extremolyte cyclic 2,3-diphosphoglycerate using Thermus thermophilus as a whole-cell factory

2020

Abstract:
Pseudomonas aeruginosa Biofilm Dispersion by the Human Atrial Natriuretic Peptide.

Abstract:
Spinning sugars in antigen biosynthesis: characterization of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases.

Abstract:
Highly thermostable carboxylic acid reductases generated by ancestral sequence reconstruction

Abstract:
A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity

Abstract:
Drug screening to identify compounds to act as co-therapies for the treatment of pathogenic Burkholderia

Abstract:
Spinning sugars in antigen biosynthesis: a direct study of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases

Abstract:
Structure and function of N-acetylglucosamine kinase illuminates the catalytic mechanism of ROK kinases

Abstract:
Broad-spectrum in vitro activity of macrophage infectivity potentiator inhibitors against Gram-negative bacteria and Leishmania major.

Abstract:
Pseudomonas aeruginosa Biofilm Dispersion by the Human Atrial Natriuretic Peptide.

Abstract:
Spinning sugars in antigen biosynthesis: characterization of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases.

Abstract:
Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species

Abstract:
A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity.

Abstract:
Highly thermostable carboxylic acid reductases generated by ancestral sequence reconstruction

Abstract:
Molecular features of lipoprotein CD0873: a potential vaccine against the human pathogen Clostridioides difficile.

Abstract:
Zoonoses under our noses.

Abstract:
The molecular basis of protein toxin HicA-dependent binding of the protein antitoxin HicB to DNA.

Abstract:
A miniaturized peptidyl-prolyl isomerase enzyme assay.

Abstract:
Structural characterisation of the capsular polysaccharide expressed by Burkholderia thailandensis strain E555:: wbiI (pKnock-KmR) and assessment of the significance of the 2-O-acetyl group in immune protection.

Abstract:
Woronin body-based sealing of septal pores.

Abstract:
Development, synthesis and structure-activity-relationships of inhibitors of the macrophage infectivity potentiator (Mip) proteins of Legionella pneumophila and Burkholderia pseudomallei.

Abstract:
Structural and biochemical characterisation of Archaeoglobus fulgidus esterase reveals a bound CoA molecule in the vicinity of the active site

Abstract:
Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors

Abstract:
Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors.

Abstract:
Pseudomonas aeruginosa Expresses a Functional Human Natriuretic Peptide Receptor Ortholog: Involvement in Biofilm Formation.

Abstract:
Unraveling the B. pseudomallei Heptokinase WcbL: from Structure to Drug Discovery

Abstract:
A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins

Abstract:
Determination of protein-ligand interactions using differential scanning fluorimetry.

Abstract:
The HicA toxin from Burkholderia pseudomallei has a role in persister cell formation.

Abstract:
Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei

Abstract:
Characterization of the Burkholderia pseudomallei K96243 capsular polysaccharide I coding region

Abstract:
Myosin-5, kinesin-1 and myosin-17 cooperate in secretion of fungal chitin synthase.

Abstract:
A Burkholderia pseudomallei macrophage infectivity potentiator-like protein has rapamycin-inhibitable peptidylprolyl isomerase activity and pleiotropic effects on virulence.

Abstract:
A novel FK-506-binding-like protein that lacks peptidyl-prolyl isomerase activity is involved in intracellular infection and in vivo virulence of Burkholderia pseudomallei.

Abstract:
Glycosylation of DsbA in Francisella tularensis subsp. Tularensis

Abstract:
The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development

Abstract:
The structure of a Burkholderia pseudomallei immunophilin-inhibitor complex reveals new approaches to antimicrobial development.

Abstract:
The fibroblast growth factor (FGF) - FGF receptor complex: Progress towards the physiological state

Abstract:
Asymmetry in the multiprotein systems of molecular biology

Abstract:
Asymmetry in the multiprotein systems of molecular biology

Abstract:
THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET

Abstract:
THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET

Abstract:
Structure and function of sedoheptulose-7-phosphate isomerase from Burkholderia pseudomallei, an unusual metalloenzyme

Abstract:
THE BURKHOLDERIA PSEUDOMALLEI MIP PROTEIN, a VIRULENCE FACTOR AND DRUG TARGET

Abstract:
A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity

Abstract:
Drug screening to identify compounds to act as co-therapies for the treatment of pathogenic Burkholderia

Abstract:
Spinning sugars in antigen biosynthesis: a direct study of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases

Abstract:
Structure and function of N-acetylglucosamine kinase illuminates the catalytic mechanism of ROK kinases

Abstract:
Survivor bias drives overestimation of stability in reconstructed ancestral proteins

Abstract:
Synuclein plasticity: the Achilles’ heel of nerve function linked to the onset of Parkinson’s disease

Abstract:
Broad-spectrum in vitro activity of macrophage infectivity potentiator inhibitors against Gram-negative bacteria and Leishmania major.

Abstract:
Pseudomonas aeruginosa Biofilm Dispersion by the Human Atrial Natriuretic Peptide.

Abstract:
Spinning sugars in antigen biosynthesis: characterization of the Coxiella burnetii and Streptomyces griseus TDP-sugar epimerases.

Abstract:
Synthetic Biology for Green Chemistry: Building in Vivo Enzymatic Cascades Using Carboxylic Acid Reductases (CARs)

Abstract:
Drug screening to identify compounds to act as co-therapies for the treatment of Burkholderia species

Abstract:
Production of the extremolyte cyclic 2,3-diphosphoglycerate using Thermus thermophilus as a whole-cell factory

Abstract:
Defining the O-antigen biosynthetic pathways in zoonotic Coxiella burnetii: Studies of dTDP-sugar biosynthesis and LPS extraction

Abstract:
A universal fluorescence-based toolkit for real-time quantification of DNA and RNA nuclease activity.

Abstract:
Ancestral sequence reconstruction as an accessible tool for the engineering of biocatalyst stability

Abstract:
Highly thermostable carboxylic acid reductases generated by ancestral sequence reconstruction

Abstract:
Highly thermostable carboxylic acid reductases generated by ancestral sequence reconstruction

Abstract:
Molecular features of lipoprotein CD0873: a potential vaccine against the human pathogen Clostridioides difficile.

Abstract:
Nucleases and histone acetyltransferases in DNA repair and immune diversity

Abstract:
Zoonoses under our noses.

Abstract:
The molecular basis of protein toxin HicA-dependent binding of the protein antitoxin HicB to DNA.

Abstract:
A miniaturized peptidyl-prolyl isomerase enzyme assay.

Abstract:
Structural characterisation of the capsular polysaccharide expressed by Burkholderia thailandensis strain E555:: wbiI (pKnock-KmR) and assessment of the significance of the 2-O-acetyl group in immune protection.

Abstract:
Woronin body-based sealing of septal pores.

Abstract:
Development, synthesis and structure-activity-relationships of inhibitors of the macrophage infectivity potentiator (Mip) proteins of Legionella pneumophila and Burkholderia pseudomallei.

Abstract:
Structural and biochemical characterisation of Archaeoglobus fulgidus esterase reveals a bound CoA molecule in the vicinity of the active site

Abstract:
Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors

Abstract:
Achieving high signal-to-noise in cell regulatory systems: Spatial organization of multiprotein transmembrane assemblies of FGFR and MET receptors.

Abstract:
Asymmetry in the multiprotein systems of molecular biology

Abstract:
Pseudomonas aeruginosa Expresses a Functional Human Natriuretic Peptide Receptor Ortholog: Involvement in Biofilm Formation.

Abstract:
Unraveling the B. pseudomallei Heptokinase WcbL: from Structure to Drug Discovery

Abstract:
A structural biology approach enables the development of antimicrobials targeting bacterial immunophilins

Abstract:
Determination of protein-ligand interactions using differential scanning fluorimetry.

Abstract:
The HicA toxin from Burkholderia pseudomallei has a role in persister cell formation.

Abstract:
Identification of type II toxin-antitoxin modules in Burkholderia pseudomallei

Abstract:
Characterization of the Burkholderia pseudomallei K96243 capsular polysaccharide I coding region

Abstract:
Myosin-5, kinesin-1 and myosin-17 cooperate in secretion of fungal chitin synthase.