Selectivity by small-molecule inhibitors of protein interactions can be driven by protein surface fluctuations.

ABSTRACT: Small-molecules that inhibit interactions between specific pairs of proteins have long represented a promising avenue for therapeutic intervention in a variety of settings. Structural studies have shown that in many cases, the inhibitor-bound protein adopts a conformation that is distinct from its unbound and its protein-bound conformations. This plasticity of the protein surface presents a major challenge in predicting which members of a protein family will be inhibited by a given ligand. Here, we use biased simulations of Bcl-2-family proteins to generate ensembles of low-energy conformations that contain surface pockets suitable for small molecule binding. We find that the resulting conformational ensembles include surface pockets that mimic those observed in inhibitor-bound crystal str

SUBMITTER: Johnson DK 

PROVIDER: S-EPMC4338137 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature