Cryo-EM structure of a dimeric B-Raf:14-3-3 complex reveals asymmetry in the active sites of B-Raf kinases

摘要: Raf kinases are important cancer drug targets. Paradoxically, many B-Raf inhibitors induce the activation of kinases. Cryo-electron microscopy structural analysis a phosphorylated kinase domain dimer in complex with dimeric 14-3-3, at resolution ~3.9 angstroms, shows an asymmetric arrangement which one is canonical "active" conformation. The distal segment C-terminal tail this interacts with, and blocks, active site cognate arrangement. Deletion reduces activity. unexpected quaternary architecture illustrates how paradoxical by reflects innate mechanism, 14-3-3 facilitating inhibition while maintaining activity other. Conformational modulation these contacts may provide new opportunities for inhibitor development.