Crystal Structure Reveals the Full Ras–Raf Interface and Advances Mechanistic Understanding of Raf Activation

Ras and Raf-kinase interact through the Ras-binding (RBD) cysteine-rich domains (CRD) of Raf to signal mitogen-activated protein kinase pathway, yet molecular mechanism leading activation has remained elusive. We present 2.8 Å crystal structure HRas–CRaf-RBD_CRD complex showing Ras–Raf interface as a continuous surface on Ras, seen in KRas–CRaf-RBD_CRD structure. In dynamics simulations dimer model formed ?4–?5 interface, CRD is dynamic located between two protomers, poised for direct or allosteric modulation functionally relevant regions Raf. propose which binding involved release autoinhibition while dimerizes promote platform amplification, with Raf-CRD centrally impact regulation function.