Professor Guy Dodson

01904 328264
E-mail: ggd500@york.ac.uk

Structural and chemical factors in enzyme mechanisms

Enzyme reactions are often the key component in many biochemical and biological processes. The stereochemical arrangements of their catalytic sites and specificity pockets are an ideal focus for x-ray crystallographic analysis. Structural studies on enzymes are being undertaken on members of the newly identified Ntn-hydrolase family. Additional features of this family are its extensive sequence variation and its property of auto-catalytic self activation, now being studied with mutant precursors.

The analysis of a protease and its nhibitor complex is being undertaken at very high resolution. With this data the accuracy of the atomic parameters in this system makes it possible to carry out molecular calculations to investigate how intrinsic motions relate to the catalytic mechanism.

Insulin structure, sequence and behaviour

The molecular structure of insulin still raises important questions in relation to its function, evolution and its use in diabetes therapy. There are studies on the structural and chemical factors that govern the hormone's stability, in particular its property of fibre formation.
Recent studies on chiral mutants have enabled us to dissect the hormone’s structural behaviour in the insulin producing cell during biosynthesis and in receptor binding.

Insulin's evolution is becoming clearer with the knowledge of genomic sequences, these are identifying early members of the family and presenting new candidates for structural and biological study.

Selected Publications

  • Insulin at pH 2: Structural Analysis of the conditions Promoting Insulin Fibre Formation.
    J L Whittingham, D J Scott, K Chance, A Wilson, J Finch, J Brange and G G Dodson, J Mol Biol, 2002, 318, 479-490.
  • Crystallographic and solution studies of N-lithocholyl insulin: a new generation of prolonged-acting human insulins.
    J L Whittingham, I Jonassen, S Havelund, S M Roberts, E J Dodson, C S Verma, A J Wilkinson and G G Dodson, Biochemistry, 2004, 20, 5987-95.
  • The crystal structure of the globular domain of sheep prion protein.
    G Dodson, L F Haire, N Vasisht and S M Whyte, J. Mol. Biol., 2004, 336, 1175-1183.
  • Prion and water: tight and dynamical hydration sites have a key role in structural stability.
    A De Simone, G G Dodson, C S Verma, A Zagar, F Freternali, Proc Natl Acd Sci USA, 2005, 102, 7535-40.