Allosteric coupling asymmetry mediates paradoxical activation of BRAF by type II inhibitors.

ABSTRACT: The type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at subsaturating concentrations. Activation is mediated by induction of BRAF dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking BRAF dimerization and conformation, we built an allosteric model of inhibitor-induced dimerization that resolves the allosteric contributions of inhibitor binding to the two active sites of the dimer, revealing key differences between type I and type II RAF inhibitors. For type II inhibitors the allosteric coupling between inhibitor binding and BRAF dimerization is distributed asymmetrically across the two dimer binding sites, with binding to the first site dominating the allostery. This asymmetry results in efficie

SUBMITTER: Rasmussen DM 

PROVIDER: S-EPMC11093583 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature