Atomic Resolution Mechanism of GTP Recognition by GTPase

Ras superfamily GTPases act as molecular switches that generally cycle between a GDP-bound “off” state and GTP-bound “on” state. The conformational changes associated with these different states are involved in the regulation of multiple cellular processes. Despite significant efforts to directly target activity, no anti-Ras drugs have been developed taken into clinic. Being nightmare for drug developers, it is believed they “undruggable” due high binding affinity GTP relatively smooth structure proteins devoid any deep pocket where small molecule could bind. Illustrating mechanism GTPase at atomistic details desirable but timescale inaccessible via computer simulations. presentation aims elucidate atomistically detailed isoforms by combining extensive unbiased classical dynamics simulations Markov model analysis. simulation captures spontaneous recognition events explain role flexible modulating event.