Dr Bill Broadhurst

Photo of Dr Bill Broadhurst

MA (Oxon), DPhil (Oxon)

Official Fellow; Member of the College Council; Acting Tutor for Admissions in Science; Acting Tutor; Director of Studies in Natural Sciences (Biological and Physical)
University Lecturer in the Department of Biochemistry

Biography

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

Details of his research.


Teaching Interests

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 metabolism;

(d) Part II Biochemistry on enzymes and protein dynamics.


Research

(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 9, 2325.

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.

(C) Other work

The following articles resulted from collaborations with colleagues or focused on method development.

(1) Frei, J.N, Broadhurst, R.W., Bostock, M.J., Solt, A., Jones, A.J.Y., Gabriel, F., Tandale, A., Shrestha, B. & Nietlispach, D. (2020) Conformational plasticity of ligand-bound and ternary GPCR complexes studies by 19F NMR of the beta-1-adrenergic receptor. Nature Communications 11, 669.

(2) Kedrov, A., Hellawell, A.M., Klosin, A., Broadhurst, R.W., Kunji, E.R.S. & Muller, D.J. (2010) Probing the interactions of carboxy-atractyloside and atractyloside with the yeast mitochondrial ADP/ATP carrier. Structure 18, 39-46.

(3) Cheung, M.S., Maguire, M.L., Stevens, T.J. & Broadhurst, R.W. (2010) DANGLE: a Bayesian inferential method for predicting protein backbone dihedral angles and secondary structure. Journal of Magnetic Resonance 202, 223-233.

(4) Kolocouris, A., Zikos, C. & Broadhurst, R.W. (2007) 19F NMR detection of the complex between amantadine and the receptor portion of the Influenza A M2 ion channel in DPC micelles. Bioorganic and Medicinal Chemistry Letters 17, 3947-3952.

(5) Lummis, S.C., Beene, D.L., Lee, L.W., Lester, H.A., Broadhurst, R.W., Dougherty, D.A. (2005) Cis-trans isomerisation at a proline opens the pore of a neurotransmitter-gated ion channel. Nature 438, 248-252.

(6) Allen, M.D., Broadhurst R.W., Solomon, R.G. & Perham, R.N. (2005) Interaction of the E2 and E3 components of the pyruvate dehydrogenase multienzyme complex of Bacillus stearothermophilus : use of a truncated protein domain in NMR spectroscopy. FEBS Journal 272, 259-268.

(7) Peto, H., Stott, K., Sunde, M. & Broadhurst, R.W. (2004) Backbone dynamics of oxidised and reduced forms of human atrial natriuretic peptide. Journal of Structural Biology 148, 214-225.

(8) Kolocouris, A., Hansen, R.K. & Broadhurst, R.W. (2004) Interaction between an amantadine analogue and the transmembrane portion of the Influenza A M2 protein in liposomes probed by 1H NMR spectroscopy of the ligand. Journal of Medicinal Chemistry 47, 4975-4978.

(9) Hansen, R.K., Broadhurst, R.W., Skelton, P.C. & Arkin, I.T. (2002) Hydrogen/deuterium exchange of hydrophobic peptides in model membranes by electrospray ionization mass spectrometry. Journal of the American Society for Mass Spectrometry 13, 1376-1287.

(10) Bolton, D., Evans, P.A., Stott, K. & Broadhurst, R.W. (2001) Structure and properties of a dimeric N-terminal fragment of human ubiquitin. Journal of Molecular Biology 314, 773-787.

(11) Tozawa, K., Broadhurst, R.W., Raine, A.R., Fuller, C., Alvarez, A., Guillen, G., Padron, G. & Perham, R.N. (2001) Solution structure of the lipoyl domain of the chimeric dihydrolipoyl dehydrogenase P64K from Neisseria meningitidis. European Journal of Biochemistry 268, 4908-4917.

(12) Reche, P.A., Howard, M.J., Broadhurst, R.W. & Perham, R.N. (2000) Heteronuclear NMR studies of the specificity of the post-translational modification of biotinyl domains by biotinyl protein ligase. FEBS Letters 479, 93-98.

(13) Roberts, E.L., Shu, N., Howard, M.J., Broadhurst, R.W., Chapman-Smith, A., Wallace, J.C., Morris, T., Cronan Jr, J.E. & Perham, R.N. (1999) Solution structures of apo and holo biotinyl domains from acetyl coenzyme A carboxylase of Escherichia coli determined by triple-resonance nuclear magnetic resonance spectroscopy. Biochemistry 38, 5045-5053.

(14) Xia, Z., Broadhurst, R.W., Laue, E.D., Bryant, D.A., Golbeck, J.H. & Bendall, D.S. (1998) Structure and properties in solution of PsaD, an extrinsic polypeptide of photosystem I. European Journal of Biochemistry 255, 309-316.

(15) Howard, M.J., Fuller, C., Broadhurst, R.W., Perham, R.N., Tang, J.-G., Quinn, J., Diamond, A.G. & Yeaman, S.J. (1998) Three dimensional solution structure of the major autoantigen in primary biliary cirrhosis. Gastroenterology 115, 139-146.

(16) Nietlispach, D., Clowes, R.T., Broadhurst, R.W., Ito, Y., Keeler, J., Kelley, M., Ashurst, J., Oschkinat, H., Domaille, P.J. & Laue, E.D. (1996) An approach to the structure determination of larger proteins using triple-resonance NMR experiments in conjunction with random fractional deuteration. Journal of the American Chemical Society 118, 407-415.

(17) Smith, B.O., Ito, Y., Raine, A.R.C., Teichmann, S., Ben-Tovim, L., Nietlispach, D., Broadhurst, R.W., Terada, T., Kelley, M., Oschkinat, H., Shibata, T., Yokoyama, S. & Laue, E.D. (1996) An approach to global fold determination using limited NMR data from larger proteins selectively protonated at specific residue types. Journal of Biomolecular NMR 8, 360-368.

(18) Wallis, N.G., Allen, M.D., Broadhurst, R.W., Lessard, I & Perham, R.N. (1996) Recognition of a surface loop of the lipoyl domain underlies substrate channelling in the pyruvate dehydrogenase multienzyme complex. Journal of Molecular Biology 263, 463-474.

(19) Ricaud, P.M., Howard, M.J., Roberts, E.L., Broadhurst, R.W. & Perham, R.N. (1996) Three dimensional structure of the lipoyl domain from the dihydrolipoyl succinyl transferase component of the 2-oxoglutarate dehydrogenase multienzyme complex of Escherichia coli. Journal of Molecular Biology 264, 179-190.

(20) Winder, S.L., Broadhurst, R.W. & Hore, P.J. (1995) Photo-CIDNP of amino-acids and proteins : effects of competition for flavin triplets. Spectrochimica Acta A 51, 1753-1761.

(21) Taddei, N., Buck, M., Broadhurst, R.W., Stefani, M., Ramponi, M. & Dobson, C.M. (1994) Equilibrium unfolding studies of horse muscle phosphatase. European Journal of Biochemistry 225, 811-817.

(22) Teuten, A.J., Broadhurst, R.W., Smith, R.A.G. & Dobson, C.M. (1993) Characterization of structural and folding properties of streptokinase by NMR spectroscopy. Biochemical Journal 290, 313-319.

(23) Hore, P.J. & Broadhurst, R.W. (1993) Photo-CIDNP of biopolymers. Progress in NMR Spectroscopy 25, 345-402.

(24) Alexandrescu, A.T., Broadhurst, R.W., Wormald, C., Chyan, C.L., Dobson, C.M. & Baum, J. (1992) 1H-NMR assignments and local microenvironments of aromatic residues in bovine, human and guinea pig variants of a-lactalbumin. European Journal of Biochemistry 210, 699-709.

(25) Broadhurst, R.W., Dobson, C.M., Hore, P.J., Radford, S.E. & Rees, M.L. (1991) A photo-chemically induced dynamic nuclear polarization study of denatured states of lysozyme. Biochemistry 30, 405-412.

(26) Broadhurst, R.W., Hoff, A.J. & Hore, P.J. (1986) Interpretation of the polarized electron paramagnetic resonance signal of plant photosystem I. Biochemica Et Biophysica Acta 852, 106-111.


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