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.We thank our colleagues Alicia Higueruelo, Douglas Pires, Bernardo Ochoa and Chris Radoux for helpful comments and discussions. D.B.A is the recipient of a C. J. Martin Research Fellowship from the National Health and Medical Research Council of Australia (APP1072476). H.J. is supported by a CASE Studentship from the UCB and the Biotechnology and Biological Sciences Research Council (BBSRC) (Grant: BB/J500574/1). T.L.B. receives funding from University of Cambridge and The Wellcome Trust for facilities and support.This is the accepted manuscript of a paper published in Progress in Biophysics and Molecular Biology (Jubb H, Blundell TL, Ascher DB, Progress in Biophysics and Molecular Biology 2015, doi:10.1016/j.pbiomolbio.2015.01.009). The final version is available at http://dx.doi.org/10.1016/j.pbiomolbio.2015.01.009