NMR-Derived Conformational Ensemble of State 1 of Activated Ras Reveals Insights into a Druggable Pocket.

The lack of apparent pockets in the ground conformation of Ras has long challenged the rational design of inhibitors against this oncogenic protein. The sparsely populated, transiently formed state 1 of activated Ras, on the other hand, shows appreciable surface roughness and is increasingly recognized as a potential target for drug discovery. State 1, however, is extremely flexible, and a static structure cannot fully unveil its conformational space that can be exploited for drug design. Here, we present a conformational ensemble of state 1 that was derived using chemical shift-based modeling. The ensemble reveals the intrinsic plasticity of a druggable pocket in state 1 and demonstrates the mechanism of conformational selection for inhibitor recognition. The large set of structural templates in the ensemble, providing a comprehensive description of thermally accessible pocket conformations, is expected to significantly aid the rational design of anti-Ras drugs.