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Titolo:
Ras-mediated cleavage of a GTP analogue by a novel mechanism
Autore:
Gail, R; Costisella, B; Ahmadian, MR; Wittinghofer, A;
Indirizzi:
Max Planck Inst Mol Physiol, Abt Strukturelle Biol, D-44227 Dortmund, Germany Max Planck Inst Mol Physiol Dortmund Germany D-44227 7 Dortmund, Germany Univ Dortmund, Fachbereich Chem, D-44227 Dortmund, Germany Univ Dortmund Dortmund Germany D-44227 h Chem, D-44227 Dortmund, Germany
Titolo Testata:
CHEMBIOCHEM
fascicolo: 7-8, volume: 2, anno: 2001,
pagine: 570 - 575
SICI:
1439-4227(20010803)2:7-8<570:RCOAGA>2.0.ZU;2-A
Fonte:
ISI
Lingua:
ENG
Soggetto:
SUBSTRATE-ASSISTED CATALYSIS; C-HA-RAS; G-PROTEIN; HYDROLYSIS; P21; COMPLEXITY; ONCOGENES; MUTATIONS; MUTANTS; TUMORS;
Keywords:
antitumor agents; hydrolases; Ras proteins; substrate-assisted catalysis;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
25
Recensione:
Indirizzi per estratti:
Indirizzo: Gail, R Max Planck Inst Mol Physiol, Abt Strukturelle Biol, Otto Hahn Str 11, D-44227 Dortmund, Germany Max Planck Inst Mol Physiol Otto Hahn Str 11 Dortmund Germany D-44227
Citazione:
R. Gail et al., "Ras-mediated cleavage of a GTP analogue by a novel mechanism", CHEMBIOCHEM, 2(7-8), 2001, pp. 570-575

Abstract

The small guanosine triphosphate (GTP) binding protein Ras is involved in many cellular signal transduction processes leading to cell growth, differentiation and apoptosis. Mutations in ras genes are found in a large number of human tumours. GTP hydrolysis, the process that normally leads to the transition of the Ras protein from the active (GTP-bound) form to the inactive (GDP-bound) form is impaired due to these oncogenic mutations. In contrast, the GTP analogue 3,4-diaminobenzophenone(DASP)-phosphoramidate-GTP, a substrate for GTP-binding proteins, enables switching to the inactive GDP form in both wild-type and oncogenic Ras. Here we show by HPLC, mass spectrometry and NMR spectroscopy that the mechanism of this DABP-GTPase reaction isdifferent from the physiological GTPase reaction. The gamma -phosphate group is not attacked by a nucleophilic water molecule, but rather by,the aromatic amino group of the analogue, which leads to the generation of a stablecyclic diamidate product, These findings, hove potential implications for the development of anti-Ras drugs.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/01/20 alle ore 10:34:49