1x1r
Crystal structure of M-Ras in complex with GDPCrystal structure of M-Ras in complex with GDP
Structural highlights
FunctionRASM_MOUSE May serve as an important signal transducer for a novel upstream stimuli in controlling cell proliferation. Weakly activates the MAP kinase pathway (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedAlthough some members of Ras family small GTPases, including M-Ras, share the primary structure of their effector regions with Ras, they exhibit vastly different binding properties to Ras effectors such as c-Raf-1. We have solved the crystal structure of M-Ras in the GDP-bound and guanosine 5'-(beta,gamma-imido)triphosphate (Gpp(NH)p)-bound forms. The overall structure of M-Ras resembles those of H-Ras and Rap2A, except that M-Ras-Gpp(NH)p exhibits a distinctive switch I conformation, which is caused by impaired intramolecular interactions between Thr-45 (corresponding to Thr-35 of H-Ras) of the effector region and the gamma-phosphate of Gpp(NH)p. Previous 31P NMR studies showed that H-Ras-Gpp(NH)p exists in two interconverting conformations, states 1 and 2. Whereas state 2 is a predominant form of H-Ras and corresponds to the "on" conformation found in the complex with effectors, state 1 is thought to represent the "off" conformation, whose tertiary structure remains unknown. 31P NMR analysis shows that free M-Ras-Gpp(NH)p predominantly assumes the state 1 conformation, which undergoes conformational transition to state 2 upon association with c-Raf-1. These results indicate that the solved structure of M-Ras-Gp-p(NH)p corresponds to the state 1 conformation. The predominance of state 1 in M-Ras is likely to account for its weak binding ability to the Ras effectors, suggesting the importance of the tertiary structure factor in small GTPase-effector interaction. Further, the first determination of the state 1 structure provides a molecular basis for developing novel anti-cancer drugs as compounds that hold Ras in the state 1 "off" conformation. Crystal structure of M-Ras reveals a GTP-bound "off" state conformation of Ras family small GTPases.,Ye M, Shima F, Muraoka S, Liao J, Okamoto H, Yamamoto M, Tamura A, Yagi N, Ueki T, Kataoka T J Biol Chem. 2005 Sep 2;280(35):31267-75. Epub 2005 Jun 30. PMID:15994326[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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