SEMINAR: Divergent Allosteric Mechanisms in Two Classes of Potential Drug Targeted Proteins

Malcolm Walkinshaw was awarded his PhD from Edinburgh University and had post-doc appointments in the US and Germany working on protein crystallography. He led a structure-based drug discovery group in Sandoz (now Novartis) in Basel for ten years before returning to Edinburgh in 1995 to take up the chair of Structural Biochemistry. In 2007 he was appointed Director of the Centre for Translational and Chemical Biology which provides access to a wide range of biophysical techniques. His main research interests are related to protein-ligand interactions and drug discovery.

Divergent Allosteric Mechanisms in Two Classes of Potential Drug Target Proteins The talk will explore two very different allosteric mechanisms. A series of structures of pyruvate kinase in different liganded states will be presented that provide some interesting insights into the two-state conformational switching mechanism originally proposed in the Monod/Wyman/Changeux (MWC) model. A rather different model of allostery is required to explain the effects observed in the Hsp90-binding immunophilin cyclophilin 40 (Cyp40). Biophysical and enzymatic studies show that binding a peptide to the TPR domain has an effect at the remote enzyme active site. These results will be discussed in terms of the available molecular dynamics and structural data.