The energetic and allosteric landscape for KRAS inhibition.

ABSTRACT: Thousands of proteins have been validated genetically as therapeutic targets for human diseases¹. However, very few have been successfully targeted, and many are considered 'undruggable'. This is particularly true for proteins that function via protein-protein interactions-direct inhibition of binding interfaces is difficult and requires the identification of allosteric sites. However, most proteins have no known allosteric sites, and a comprehensive allosteric map does not exist for any protein. Here we address this shortcoming by charting multiple global atlases of inhibitory allosteric communication in KRAS. We quantified the effects of more than 26,000 mutations on the folding of KRAS and its binding to six interaction partners. Genetic interactions in double mutants enabled

SUBMITTER: Weng C 

PROVIDER: S-EPMC10866706 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature