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.

An integrated workflow for crosslinking mass spectrometry

“…This is an exciting result, as it highlights a novel and essential role for Mcm2 C‐terminus in a late step of MCM2‐7 double‐hexamer formation (Barbon et al , in preparation), a process that is only poorly understood. Moreover, the CLMS data show that the Mcm2 C‐terminus is involved in a network of interactions with flexible domains of Orc6, Orc2 and Mcm5, indicating dynamics at the Mcm2‐Mcm5 DNA entry gate (Samel et al , ), which could represent an ideal target for the development of inhibitors with potential as anti‐cancer therapy (Gardner et al , ), as dynamic interactions have improved druggability characteristics over stable protein interactions (Ulucan et al , ; Jubb et al , ). Indeed, expressing Mcm2‐7ΔC2 causes dominant lethality (Fig C).…”

Small-molecule binding sites to explore protein–protein interactions in the cancer proteome

“…We identified several proteins whose overexpression correlate with patient outcome that occurred at protein-protein interfaces. This discovery is highly significant as protein-protein interactions have been historically challenging due to the lack of well-defined binding sites at protein-protein interfaces (65,66). Protein-protein interfaces can offer an opportunity to develop highly selective compounds since many of these interfaces are structurally unique.…”

Computational prediction of protein interfaces: A review of data driven methods

“…But individual proteins do not function alone; they must interact with other molecules to carry out their cellular roles. Alterations in protein-protein interfaces often lead to disease, and hence protein interfaces have become one of the most popular new targets for rational drug design (Jubb, Blundell, & Ascher, 2015; Rask-Andersen, Almén, & Schiöth, 2011). In addition to practical applications in drug design, reliable identification of protein-protein interfaces is important for basic research on the mechanisms of macromolecular recognition.…”