Mechanism of Dimer Selectivity and Binding Cooperativity of BRAF Inhibitors.

ABSTRACT: Aberrant signaling of BRAF^V600E is a major cancer driver. Current FDA-approved RAF inhibitors selectively inhibit the monomeric BRAF^V600E and suffer from tumor resistance. Recently, dimer-selective and equipotent RAF inhibitors have been developed; however, the mechanism of dimer selectivity is poorly understood. Here, we report extensive molecular dynamics (MD) simulations of the monomeric and dimeric BRAF^V600E in the apo form or in complex with one or two dimer-selective (PHI1) or equipotent (LY3009120) inhibitor(s). The simulations uncovered the unprecedented details of the remarkable allostery in BRAF^V600E dimerization and inhibitor binding. Specifically, dimerization retrains and shifts the αC helix inward and increases the flexibilit

SUBMITTER: Clayton J 

PROVIDER: S-EPMC10760002 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature