1CLU

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

Summary for 1CLU

• Entry DOI: 10.2210/pdb1clu/pdb
• Descriptor: TRANSFORMING PROTEIN P21/H-RAS-1, MAGNESIUM ION, 3-AMINOBENZOPHENONE-4-YL-AMINOHYDROXYPHOSPHINYLAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (4 entities in total)
• Functional Keywords: gtp hydrolase, signal transduction, cancer, g-domain, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 19655.99

Authors

Ahmadian, M.R.,Zor, T.,Vogt, D.,Kabsch, W.,Selinger, Z.,Wittinghofer, A.,Scheffzek, K. (deposition date: 1999-05-03, release date: 1999-05-28, Last modification date: 2023-08-09)

Primary citation

Ahmadian, M.R.,Zor, T.,Vogt, D.,Kabsch, W.,Selinger, Z.,Wittinghofer, A.,Scheffzek, K.
Guanosine triphosphatase stimulation of oncogenic Ras mutants.
Proc.Natl.Acad.Sci.USA, 96:7065-7070, 1999

PubMed Abstract: 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.

PubMed: 10359839
DOI: 10.1073/pnas.96.12.7065

Experimental method

X-RAY DIFFRACTION (1.7 Å)