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Structural Biology and Bioinformatics

Research Groupings: Structural and molecular cell biology | Developmental and regenerative biology and medicine

Professor Sir Tom completed his term of thirteen years as Sir William Dunn Professor of Biochemistry and Head of Department on 30th September 2009. He has been appointed Director of Research and Professor Emeritus. He will continue to conduct research in structural and computational biology. In July 2009 he took up the post of Chair of the Biotechnology and Biological Sciences Research Council, a non-executive part-time appointment.

Research
We are interested in determining the three-dimensional structures of proteins involved in receptor activation and intracellular transduction of signals. Our research involves the expression, characterisation, crystallisation, X-ray analysis and NMR structure determination of individual components and multi-protein complexes.

For example, 3D structure of the fibroblast growth factor receptor (FGFR), in complex with the FGF and heparin (right), reveals how FGF induces dimerisation of the receptor kinase, and why heparin is important for signalling. We are also studying receptors for nerve growth factor, hepatocyte growth factor, as well as complexes of protein kinases with substrates, inhibitory and other regulatory proteins.

We have been involved in the structural biology of multiprotein complexes involved in repair of double strand breaks, including those involved in Non-Homologous End Joining (for example the complex of Xrcc4 and the DNA ligase; left) and homologous recombination (for example, the complex between the breast cancer related gene BRCA2 with the recombinase, Rad51).

The group is interested in microbial pathways. For example, in collaboration with Chris Abell in Chemistry and Alison Smith in Plant Sciences, we have defined the 3D structures of all of the enzymes in the pantothenate pathway using X-ray analysis. With [the late] Joe Spencer in Chemistry we have looked at enzymes involved in biosynthesis of vancomycin and aminoglycoside antibiotics. Our interests in three-dimensional structure have led to developments in structural bioinformatics, including databases for protein families such as HOMSTRAD and algorithms for fold recognition (FUGUE), comparative modelling (MODELLER, ORCHESTRAR) and identification of protein function (CRESCENDO). With these we can analyse the structure and function of genome sequences.

1. Pellegrini, L., Burke, D., von Delft, F., Mulloy, B. & Blundell, T.L. (2000) Crystal structure of fibroblast growth factor receptor ectodomain bound to ligand and heparin. Nature 407, 244-250.
2. Shi, J., Blundell, T.L. & Mizuguchi, K (2001) FUGUE: Sequence-structure Homology Recognition Using Environment-specific Substitution Tables and Structure-dependent Gap Penalties. J. Mol. Biol. 310, 243-257.
3. Pellegrini, L., Yu, D.S., Lo, T., Anand, S., Lee, M., Blundell, T.L. & Venkitaraman, A.R. (2002) Insights into DNA recombination from the structure of a RAD51-BRCA2 complex. Nature 420, 287-293.
4. Schmitzberger, F., Kilkenny, M.L., Lobley, C.M., Webb, M.E., Vinkovic, M., Matak-Vinkovic, D., Witty, M., Chirgadze, D.Y., Smith, A.G., Abell, C. & Blundell, T.L. (2003) Structural constraints on protein self-processing in L-aspartate-alpha-decarboxylase. EMBO J. 22, 6193-6204.