1rvd

From Proteopedia

Revision as of 14:50, 15 February 2008

H-RAS COMPLEXED WITH DIAMINOBENZOPHENONE-BETA,GAMMA-IMIDO-GTP

Overview

Interest in the guanosine triphosphatase (GTPase) reaction of Ras as a, molecular drug target stems from the observation that, in a large number, of human tumors, Ras is characteristically mutated at codons 12 or 61, more rarely 13. Impaired GTPase activity, even in the presence of GTPase, activating proteins, has been found to be the biochemical reason behind, the oncogenicity of most Gly12/Gln61 mutations, thus preventing Ras from, being switched off. Therefore, these oncogenic Ras mutants remain, constitutively activated and contribute to the neoplastic phenotype of, tumor cells. Here, we show that the guanosine 5'-triphosphate (GTP), analogue diaminobenzophenone-phosphoroamidate-GTP (DABP-GTP) is hydrolyzed, by wild-type Ras but more efficiently by frequently occurring oncogenic, Ras mutants, to yield guanosine 5'-diphosphate-bound inactive Ras and, DABP-Pi. The reaction is independent of the presence of Gln61 and is most, dramatically enhanced with Gly12 mutants. Thus, the defective GTPase, reaction of the oncogenic Ras mutants can be rescued by using DABP-GTP, instead of GTP, arguing that the GTPase switch of Ras is not irreversibly, damaged. An exocyclic aromatic amino group of DABP-GTP is critical for the, reaction and bypasses the putative rate-limiting step of the intrinsic Ras, GTPase reaction. The crystal structures of Ras-bound, DABP-beta,gamma-imido-GTP show a disordered switch I and identify the, Gly12/Gly13 region as the hydrophobic patch to accommodate the, DABP-moiety. The biochemical and structural studies help to define the, requirements for the design of anti-Ras drugs aimed at the blocked GTPase, reaction.

Disease

Known diseases associated with this structure: Bladder cancer, somatic OMIM:[190020], Costello syndrome OMIM:[190020], Thyroid carcinoma, follicular, somatic OMIM:[190020]

About this Structure

1RVD is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.

Reference

Guanosine triphosphatase stimulation of oncogenic Ras mutants., Ahmadian MR, Zor T, Vogt D, Kabsch W, Selinger Z, Wittinghofer A, Scheffzek K, Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):7065-70. PMID:10359839

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