Ras-binding domain (RBD) (RBD)

The Ras-binding domain (RBD) is a conserved structural motif, typically featuring a ubiquitin-like fold, found in various downstream effector proteins of the Ras superfamily of GTPases [UniProt: P15056, PubMed: 25533483]. Key effectors containing this domain include the Raf kinase family (A-Raf, B-Raf, C-Raf), phosphoinositide 3-kinases (PI3K), and Ral guanine nucleotide dissociation stimulators (RalGDS) [PubMed: 11046148]. The primary biological function of the RBD is to mediate the recruitment of these effectors to the plasma membrane by specifically binding to the switch regions of active, GTP-bound Ras, which subsequently triggers signaling cascades such as the MAPK/ERK and PI3K/Akt pathways [PubMed: 26140592]. In human cancers, particularly those involving KRAS, NRAS, or HRAS mutations, the constitutive activation of Ras leads to hyper-activation of these effector pathways, driving uncontrolled cell proliferation and survival [NIH: National Cancer Institute]. Therapeutic strategies targeting the RBD involve the use of Ras-mimetics or small molecules designed to sterically hinder the Ras-effector interface, thereby blocking oncogenic signaling [PubMed: 26140592]. While drugs like Rigosertib have been developed to target multiple RBDs simultaneously, achieving sufficient potency and selectivity without disrupting essential physiological Ras signaling remains a significant clinical challenge [PubMed: 30215130].

Other names

Ras-associating domainRA domainRas-binding motifRas effector-binding domain

Competitive inhibition of Ras-effector protein-protein interactions by binding to the Ras-binding domain (RBD) of effector proteins, preventing their recruitment to active Ras-GTP and blocking downstream signaling pathways [PubMed: 26140592].