Ras-binding domain of Raf kinases (RBD) (RBD)

The Ras-binding domain (RBD) of Raf kinases is a highly conserved structural motif found in A-Raf, B-Raf, and C-Raf (Raf-1) that is essential for the initiation of the MAPK/ERK signaling cascade (UniProt P04049). Its primary role is to recognize and bind to the active, GTP-bound form of Ras proteins at the plasma membrane, a process that facilitates Raf dimerization and activation (PubMed: 27149844). This interaction serves as a molecular switch that translates extracellular signals into intracellular responses governing cell growth, differentiation, and survival (NIH: PMC4915358). In the context of oncology, mutations in Ras or Raf often lead to a constitutively active RBD-Ras complex, which drives the progression of various malignancies, including lung, colorectal, and pancreatic cancers (PubMed: 27149844). Because of its central role in oncogenic signaling, the RBD is a major focus for drug discovery efforts aimed at disrupting protein-protein interactions (PPIs) (PubMed: 30104363). Therapeutic agents such as Rigosertib have been developed to act as Ras-mimetics, binding to the RBD to prevent the assembly of the Ras-Raf complex and inhibit downstream signaling (PubMed: 27149844). Despite its potential, targeting the RBD presents challenges, such as the need for high affinity to compete with the strong natural Ras-Raf bond and the risk of affecting normal cellular signaling (PubMed: 30104363). Monitoring biomarkers like KRAS or BRAF mutation status is crucial for identifying patients most likely to benefit from these targeted therapies (NIH: PMC4915358).

Other names

Raf-RBDRas-binding domainC-Raf RBDB-Raf RBDA-Raf RBD

Competitive inhibition of the protein-protein interaction between Ras-GTP and the Raf Ras-binding domain, preventing Raf recruitment to the plasma membrane and subsequent MAPK pathway activation (PubMed: 27149844).