9b4q | pdb_00009b4q

Crystal structure of RRAS2 (RAS-Related protein) bound to GMPPNP

spinqualitylabelsall models 9b4q, resolution 1.46Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9b4q is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.46Å Ligands: GNP, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease RRAS2_HUMAN Defects in RRAS2 are a cause of susceptibility to ovarian cancer (OC) [MIM:167000. The term ovarian cancer defines common malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. Function RRAS2_HUMAN It is a plasma membrane-associated GTP-binding protein with GTPase activity. Might transduce growth inhibitory signals across the cell membrane, exerting its effect through an effector shared with the Ras proteins but in an antagonistic fashion. Publication Abstract from PubMed Mutations in RAS and PI3Kalpha are major drivers of human cancer. Their interaction plays a crucial role in activating PI3Kalpha and amplifying the PI3K-AKT-mTOR pathway. Disrupting RAS-PI3Kalpha interaction enhances survival in lung and skin cancer models and reduces tumor growth and angiogenesis, although the structural details of this interaction remain unclear. Here, we present structures of KRAS, RRAS2, and MRAS bound to the catalytic subunit (p110alpha) of PI3Kalpha, elucidating the interaction interfaces and local conformational changes upon complex formation. Structural and mutational analyses highlighted key residues in RAS and PI3Kalpha impacting binding affinity and revealed isoform-specific differences at the interaction interface in RAS and PI3K isoforms, providing a rationale for their differential affinities. Notably, in the RAS-p110alpha complex structures, RAS interaction with p110alpha is limited to the RAS-binding domain and does not involve the kinase domain. This study underscores the pivotal role of the RAS-PI3Kalpha interaction in PI3Kalpha activation and provides a blueprint for designing PI3Kalpha isoform-specific inhibitors to disrupt this interaction. Structural insights into isoform-specific RAS-PI3Kalpha interactions and the role of RAS in PI3Kalpha activation.,Czyzyk D, Yan W, Messing S, Gillette W, Tsuji T, Yamaguchi M, Furuzono S, Turner DM, Esposito D, Nissley DV, McCormick F, Simanshu DK Nat Commun. 2025 Jan 9;16(1):525. doi: 10.1038/s41467-024-55766-x. PMID:39788953 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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