Modulating the Cellular Structural Interactome: Targeting Protein-Protein Interactions

Public Talk by Prof. Sir Tom L Blundell, University of Cambridge, UK
January 27, 2012
Time: 4 p.m

Abstract:

Detailed structural knowledge of the interactions between macromolecules can contribute to understanding of cellular networks. These data, which comprise the structural interactome, can augment molecular level interaction networks with information derived from the analysis of interactions in atomic detail, so allowing extension of the data by the use of comparative modelling and prediction of protein-protein interactions. Structural interactomics can provide a rich source of information on the various types of interaction between biological molecules and between these and synthetic ligands.
In this lecture I will describe databases and tools that enable the utilisation of the available structural information on protein-molecule interactions in combination with sequence and molecular interaction data. Three-dimensional information of this kind assists the validation of drug targets, the assessment of binding site druggability, the prediction of the functional effects of nsSNPs, and the design of potent and selective synthetic ligands. I will illustrate how our databases and tools can be used to explore medicinally relevant intervention within an example cellular subsystem, the fibroblast growth factor (FGF)-stimulated mitogen-activated protein kinase (MAPK) signalling pathway.
I will also describe the use of fragment-based approaches, focusing on targeting protein-protein interactions. Topics will include (i) the human recombinase, Rad51, interactions with BRCA2, inhibitors of which would be helpful in modulating DNA repair during chemo- or radiotherapy and (ii) the Met receptor interaction with HGF/SF, important in regulating metastasis.