title: Flexibility and small pockets at protein-protein interfaces: New insights into druggability.
abstract: The transient assembly of multiprotein complexes mediates many aspects of cell regulation and signalling in living organisms. Modulation of the formation of these complexes through targeting protein-protein interfaces can offer greater selectivity than the inhibition of protein kinases, proteases or other post-translational regulatory enzymes using substrate, co-factor or transition state mimetics. However, capitalising on protein-protein interaction interfaces as drug targets has been hindered by the nature of interfaces that tend to offer binding sites lacking the well-defined large cavities of classical drug targets. In this review we posit that interfaces formed by concerted folding and binding (disorder-to-order transitions on binding) of one partner and other examples of interfaces where a protein partner is bound through a continuous epitope from a surface-exposed helix, flexible loop or chain extension may be more tractable for the development of "orthosteric", competitive chemical modulators; these interfaces tend to offer small-volume but deep pockets and/or larger grooves that may be bound tightly by small chemical entities. We discuss examples of such protein-protein interaction interfaces for which successful chemical modulators are being developed.
authors: Department of Biochemistry, Sanger Building, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK.
authors: Harry
authors: H
authors: Jubb
authors: Department of Biochemistry, Sanger Building, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK.
authors: Tom L
authors: TL
authors: Blundell
authors: Department of Biochemistry, Sanger Building, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK. Electronic address: da382@cam.ac.uk.
authors: David B
authors: DB
authors: Ascher
mesh_terms: D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D025941:Protein Interaction Mapping / Q000379:methods*; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D011506:Proteins
keywords: Hotspots; Inhibitors druggability; Protein–protein interfaces