Professor Bill Hunter FRSE, FMedSci, FRSC
Chemical structure and interactions define biological events and determine how cells or organisms live and die. My research involves elucidation of the relationships that link protein structure to biological function or chemical catalysis. The broad objectives are to determine the mechanisms whereby enzymes catalyze specific, sometimes unusual biosynthetic reactions or where protein architecture regulates the transport of materials or signals across a membrane. Our results inform on basic aspects of biology and a few prized structures represent targets for early stage drug discovery. When high value targets are identified the focus is to map out the determinants of specificity and inhibition. Understanding the detailed chemical interactions between targets and small molecules allows us to advance ideas that will ultimately lead to more potent inhibitors designed to assist drug discovery or to generate reagents for further research. I have a long-term interest in targeting microbial pathogens, which present major health and veterinary problems in developing countries and more recently we are developing projects in the neurosciences area.
The major technique applied in the laboratory is single crystal X-ray diffraction (Figure 1), a mix of physics, chemistry and biochemistry, and this is aided by additional physical chemistry, molecular screening and biological techniques. Aspects of computational modeling assist our studies and productive collaborations with synthetic chemists provide valued reagents for study.
Figure 1 shows a panel of crystals being studied in the lab.
A long-term interest in pterin/folate metabolism targets the enzyme pteridine reductase (PTR1), an NADPH-dependent short-chain reductase, that participates in the salvage of pterins by parasitic trypanosomatid protozoans. PTR1 displays broad-spectrum activity with pterins and folates, provides a metabolic by-pass for inhibition of the trypanosomatid dihydrofolate reductase and compromises the use of antifolates for treatment of trypanosomiasis. Our characterization of PTR1 and numerous inhibitor complexes (Figure 2) is providing new scaffolds to aid the search for highly potent PTR1 inhibitors (3).
Fig 2. The active site of T. brucei pteridine reductase in complex with a novel inhibitor.
Our work also promotes understanding of how existing drugs work, and the success with nicotinamidase has revealed the mode of activation of a front line antituberculosis drug (4) and recently we reported the structure of an enzyme, TDR1, implicated in the activation of pro-drug antimonial compounds used to treat leishmaniaisis (5, Figure 3). TDR1 is a unique type of glutathione transferase that has evolved by gene fusion of two transferase domains. Other research seeks to dissect the architecture of membrane bound protein secretion machines and the structures of amidase effectors linked to bacterial virulence and signalling.
Fig 3. The nicotinamidase mechanism and mode of activation of a front line antituberculosis drug, pyrazinamide.
Our research has gained funding from BBSRC, The Wellcome Trust and the European Commission.
- The architecture of EssB, a Type VII secretion system integral membrane component, derived by combining crystallography and PELDOR spectroscopy. (2013) Zoltner, M., Norman, D.G., Fyfe, P.K., El Mkami, H., Palmer, T. & Hunter, W.N. Structure, 21, 595-603.
- The architecture of Trypanosoma brucei tubulin-binding cofactor B and implications for function. Fleming, J.R., Morgan, R.E., Fyfe, P.K., Kelly, S.M. & Hunter, W.N. (2013). FEBS J. 280, 3270-3280.
- Characterization of Staphylococcus aureus EssB, an integral membrane component of the type VII secretion system; crystal structure of the cytoplasmic seqment. Zoltner, M., Fyfe, P.K., Palmer, T. & Hunter, W.N. (2012). Biochemical Journal. 449, 469-477.
- New Secreted Toxins and Immunity Proteins Encoded within the Type VI Secretion System Gene Cluster of Serratia marcescens. English, G.,Trunk, K., Rao, V.A., Srikannathasan, V., Hunter, W.N. & Coulthurst, S.J. (2012). Mol. Microbiology 86, 921-936.
- Leishmania major TDR1, a unique trimeric glutathione transferase, evolved by gene duplication, diversification then fusion. Fyfe, P.K., Westrop, G.D., Silva, A., Coombs, G. & Hunter, W.N. (2012). Proc. Natl. Acad. Sci. USA. 109, 11693-11698.