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Review
. 2015 Oct;119(1):2-9.
doi: 10.1016/j.pbiomolbio.2015.01.009. Epub 2015 Feb 7.

Flexibility and small pockets at protein-protein interfaces: New insights into druggability

Harry Jubb  1 , Tom L Blundell  1 , David B Ascher  2
Affiliations
Review

Flexibility and small pockets at protein-protein interfaces: New insights into druggability

Harry Jubb et al. Prog Biophys Mol Biol. 2015 Oct.

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.

Keywords: Hotspots; Inhibitors druggability; Protein–protein interfaces.

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Figures

Fig. 1
Fig. 1
Three models of binary protein–protein interactions. (a) Preformed globular structures that interact through a discontinuous epitope with no conformational change. (b) Preformed globular structures that adopt a novel conformation in the complex. (c) Unstructured proteins that fold on binding their partners. Reproduced with permission from Blundell T.L. et al. (2006).
Fig. 2
Fig. 2
PPI involving RAD51 and its homologues. (a) The structure of RAD51 complexed with the region BRC4 of BRCA2 demonstrating the existence of two well-defined pockets on RAD51 that are occupied by side chains of the conserved FxxA motif. RAD51 is shown as grey van-der-Waals surface. BRC4 is shown in purple cartoon form. Residues within a 4 Å radius of the FxxA motif are highlighted in red on the RAD51 surface. (b) Sequences of homologous repeats in human BRCA2. (c) An equivalent view of P. furiosus RadA in a protein oligomeric filament showing the similarity of the interface with that of the RAD51 BC4 complex. The interacting oligomerisation region of the adjacent RadA protomer is shown as a purple cartoon. (d) Oligomerisation sequences of RAD51 orthologues and RadA. Reproduced with permission from Winter A. et al. (2012).
Fig. 3
Fig. 3
Residue binding modes at pairwise PPI interfaces. (a) Comparison of binding site depth utilisation by residues in different classes of pairwise PPI interface. Each point represents a residue contributed by the shortest chains in each interface pair. The abscissa indicates how deeply a residue is bound into the partner protein's surface, measured using Rinaccess (see text). The scale ranges from <2.5 Å, which represent deep binding pockets, to 10.5 Å, which represents flatness. The ordinate measures how deep the local pocket environment around the residue is, measured as the deepest partner protein atom found within 5 Å of the residue of interest. The 2D density mapping shows that peptide interfaces proportionally make better use of the concavity available to them, whereas for globular interfaces the majority of interface residues lie flat against binding surfaces of variable depth. (b) Comparison of the binding mode of the deepest bound residues from interfaces of different classes. The ordinate counts the number of interfaces with the deepest interface residue contributed at pocket classifications on the ordinate, which are based on Rinaccess (see text). Isologous homopairs refer to protomer pairs which contribute the same residues to the interface, i.e. the same protein sequence bound with 180° rotational symmetry.
Fig. 4
Fig. 4
Pocket occupation by interface residues of different secondary structures. The secondary structure of buried (a) and solvent exposed (b) interface residues occupying concavities varies by the type of interface. Together, loop and turn regions dominate the examples of pocket bound residues in solvent exposed environments, whereas buried residues bound in pockets and grooves tend to be found in helices. Interface residue data are derived from a non-redundant subset of pairwise, non-overlapping PDB interfaces.
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