1CLU

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

1CLU の概要

• エントリーDOI: 10.2210/pdb1clu/pdb
• 分子名称: TRANSFORMING PROTEIN P21/H-RAS-1, MAGNESIUM ION, 3-AMINOBENZOPHENONE-4-YL-AMINOHYDROXYPHOSPHINYLAMINOPHOSPHONIC ACID-GUANYLATE ESTER, ... (4 entities in total)
• 機能のキーワード: gtp hydrolase, signal transduction, cancer, g-domain, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 19655.99

構造登録者

Ahmadian, M.R.,Zor, T.,Vogt, D.,Kabsch, W.,Selinger, Z.,Wittinghofer, A.,Scheffzek, K. (登録日: 1999-05-03, 公開日: 1999-05-28, 最終更新日: 2023-08-09)

主引用文献

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

実験手法

X-RAY DIFFRACTION (1.7 Å)