Abstract
Ras guaosine triphosphate hydrolase (GTPase) are central to key cell signaling pathways and, when mutated, drive many cancers. Thought to be undruggable, dramatic progress has been made in the last decade in the design and screening of drugs, in large part thanks to an emerging detailed understanding of Ras conformational changes, excited/sparsely populated states, and allosteric interactions with ligands and protein-binding partners. This perspective reviews this recent progress and how it has been enabled by deep mutational scanning, solution nuclear magnetic resonance (NMR) spectroscopic studies, as well as computational modeling and simulations. We critically discuss these developments over the last 5 years, also for the GTPase-activating proteins (GAP) NF1 and plexin, effector proteins, plexin and Raf, and make suggestions on the gaps in our understanding that still exist.