Dr Bill Broadhurst
MA (Oxon), DPhil (Oxon)
Official Fellow; Member of the College Council; Acting Tutor; Director of Studies in Natural Sciences (Biological and Physical)
University Lecturer in the Department of Biochemistry
Bill Broadhurst’s enthusiasm for science was ignited at the age of seven when his father showed him what happens when a lump of metallic sodium is dropped into a bucket of water. The resulting explosion had unexpected consequences, one being his arrival as an undergraduate at University College, Oxford to study Chemistry in 1982. His interests gradually become less incendiary, leading to a DPhil on the effects of magnetic fields on free radical reactions, followed by postdoctoral work in both Oxford and Cambridge into biological applications of nuclear magnetic resonance (NMR) spectroscopy. Since becoming an Assistant Director of Research in the Department of Biochemistry in 1995, he has used NMR to investigate the structure, dynamics and interactions of proteins. He joined Emmanuel College as an Official Fellow in 2005 and became a University Lecturer in 2015.
Outside the world of work, for the last seven years in Cambridge he has been involved in the life of St James' Church, Wulfstan Way
Director of Studies for Biological Natural Sciences at Emmanuel
Supervisor for the NST1A Biology of Cells course
Supervisor for the MVST1A Molecules in Medical Science course
Lectures, practicals and examining for the Department of Biochemistry for:
(a) NST1A Mathematical Biology on calculus and the kinetics of enzyme-catalyzed reactions;
(b) MVST1A Molecules in Medical Science on thermodynamics, nutrition and bioinformatics;
(c) NST1B Biochemistry and Molecular Biology on protein structure; and
(d) Part II Biochemistry on enzymes and protein dynamics.
(A) Structural dynamics of modular polyketide synthases
Modular polyketide synthases (PKSs) are among the largest integrated enzyme complexes known, organizing clusters of catalytic domains into assembly lines which produce bioactive products that range from antibiotics to toxins. I am interested in how these systems use global conformational changes, protein-protein interfaces and protein-substrate recognition to control the production of polyketide natural product chains.
1. Moretto, L., Heylen, R., Holroyd, N., Vance, S. & Broadhurst, R.W. (2019) Modular type I polyketide synthase acyl carrier protein domains share a common N-terminally extended fold. Scientific Reports, in press.
2. Moretto, L., Vance, S., Heames, B. & Broadhurst, R.W. (2017) Dissecting how modular polyketide synthase ketoreductases interact with acyl carrier protein-attached substrates. Chemical Communications 53, 11457-11460.
3. Vance, S., Tkachenko, O., Thomas, B., Bassuni, M., Hong, H., Nietlispach, D. & Broadhurst, W. (2016) Sticky swinging arm dynamics: studies of an acyl carrier protein domain from the mycolactone polyketide synthase. Biochemical Journal 473, 1097-1110.
4. Murphy, A.C., Hong, H., Vance, S., Broadhurst, R.W. & Leadlay, P.F. (2016) Broadening substrate specificity of a chain-extending ketosynthase through a single active site mutation. Chemical Communications 52, 8373-8376.
5. Tran, L., Broadhurst, R.W., Tosin, M., Cavalli, A. & Weissman, K.J. (2010) Insights into protein-protein and enzyme-substrate interactions in modular polyketide synthases. Chemistry & Biology 17, 705-716.
6. Richter, C.D., Nietlispach D., Broadhurst R.W. & Weissman K.J. (2008) Multienzyme docking in hybrid megasynthases. Nature Chemical Biology 4, 75-81.
7. Richter, C.D., Stanmore, D.A., Miguel, R.N., Moncrieffe, M.C., Tran, L., Brewerton, S., Meersman, F., Broadhurst, R.W. & Weissman, K.J. (2007) Autonomous folding of interdomain reginos of a modular polyketide synthase. FEBS J. 274, 2196-2209.
8. Broadhurst R.W., Nietlispach D., Wheatcroft M.P., Leadlay P.F. & Weissman K.J. (2003) The structure of docking domains in modular polyketide synthases. Chemistry & Biology 10, 723-731.
(B) Protein-nucleic acid interactions
I am also interested in how NMR spectroscopy can be used to investigate the structural and dynamic properties of protein-DNA and protein-RNA complexes.
1. Short, F.L., Akusobi, C., Broadhurst, R.W. & Salmond, G.P.C. (2018) The bacterial Type III toxin-antitoxin system, ToxIN, is a dynamic protein-RNA complex with stability-dependent antiviral abortive infection activity. Scientific Reports 8, 1013.
2. Bruce, H.A., Du, D., Matak-Vinkovic, D., Bandyra, K.J., Broadhurst, R.W., Martin, E., Sobott, F., Shkumatov, A.V. & Luisi, B.F. (2018) Analysis of the natively unstructured RNA/protein-recognition core in the Escherichia coli RNA degradosome and its interactions with regulatory RNA/Hfq complexes. Nucleic Acids Research 46, 387-402.
3. Gonzales, G., Hardwick, A., Maslen, S.L., Skehel, J.M., Holmqvist, E., Vogel, J., Bateman, A., Luisi, B.F. & Broadhurst, R.W. (2017) Structure of the Escherichia coli ProQ RNA chaperone protein. RNA 23, 696-711.
4. Ali, M. & Broadhurst, R.W. (2013) Solution structure of the QUA1 dimerization domain of pXqua, the Xenopus orthology of Quaking. PLoS One, e57345.
5. Hardwick, S.W., Chan, V.S.Y., Broadhurst, R.W. & Luisi, B.F.(2011) An RNA degradosome assembly in Caulobacter crescentus. Nucleic Acids Research 39, 1449-1459.
6. Magure, M.L., Guler-Gane, G., Nietlispach, D., Raine, A.R., Zorn, A.M., Standart, N. & Broadhurst, R.W. (2005) Solution structure and backbone dynamics of the KH-QUA2 region of the Xenopus STAR/GSG quaking protein. Journal of Molecular Biology 348, 265-279.
7. Brasher, S.V., Smith , B.O., Fogh, R.H., Nietlispach, D., Thiru, A., Nielsen, P.R., Broadhurst, R.W., Ball, L.J., Murzina, N.V. & Laue, E.D. (2000) The structure of mouse HP1 suggests a unique mode of single peptide recognition by the shadow chromo domain dimer. EMBO Journal 19, 1587-1597.
8. Grasser, K.D., Teo, S.H., Lee, K.B., Broadhurst, R.W., Rees, C., Hardman, C.H. & Thomas, J.O. (1998) DNA-binding properties of the tandem HMG boxes of high-mobility-group protein 1 (HMG1). European Journal of Biochemistry 253, 787-795.
9. Ball, L.J., Murzina, N.V., Broadhurst, R.W., Raine, A.R., Archer, S.J., Stott, F.J., Murzin, A.G., Singh, P.B., Domaille, P.J. & Laue, E.D. (1997) Structure of the chromatin binding (chromo) domain from mouse modifier protein 1. EMBO Journal 16, 2473-2481.
10. Broadhurst, R.W., Hardman, C.H., Thomas, J.O. & Laue, E.D. (1995) Backbone dynamics of the A-domain of HMG1 as studied by 15N NMR spectroscopy. Biochemistry 34, 16608-16617.
11. Hardman, C.H., Broadhurst, R.W., Raine, A.R., Grasser, K.D., Thomas, J.O. & Laue, E.D. (1995) Structure of the A-domain of HMG1 and its interaction with DNA as studied by heteronuclear three-and four-dimensional NMR spectroscopy. Biochemistry 34, 16596-16607.
12. Teo, S.H., Grasser, K.D., Hardman, C.H., Broadhurst, R.W., Laue, E.D. & Thomas, J.O. (1995) Two mutations in the HMG-bos with very different structural consequences provide insights into the nature of binding to four-way junction DNA. EMBO Journal 14, 3844-3853.