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Crystal structure of M-Ras in complex with GDP

Overview

Although 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.

About this Structure

1X1R is a Single protein structure of sequence from Mus musculus with MG and GDP as ligands. Full crystallographic information is available from OCA.

Reference

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

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