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Titolo:
INHIBITION OF CYCLIN-DEPENDENT KINASES BY PURINE ANALOGS - CRYSTAL-STRUCTURE OF HUMAN CDK2 COMPLEXED WITH ROSCOVITINE
Autore:
DEAZEVEDO WF; LECLERC S; MEIJER L; HAVLICEK L; STRNAD M; KIM SH;
Indirizzi:
CNRS,BIOL STN,BP 74 F-29682 ROSCOFF FRANCE CNRS,BIOL STN F-29682 ROSCOFF FRANCE UNIV CALIF BERKELEY,DEPT CHEM BERKELEY CA 00000 UNIV CALIF BERKELEY,LAWRENCE BERKELEY NATL LAB BERKELEY CA 00000 CHARLES UNIV,INST TOXICOL & FORENS CHEM,FAC MED 1 PRAGUE CZECH REPUBLIC DEPT PLANT BIOTECHNOL,INST EXPT BOT OLOMOUC CZECH REPUBLIC
Titolo Testata:
European journal of biochemistry
fascicolo: 1-2, volume: 243, anno: 1997,
pagine: 518 - 526
SICI:
0014-2956(1997)243:1-2<518:IOCKBP>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
BUTYROLACTONE-I; PROTEIN-KINASE; CDC2 KINASE; SELECTIVE INHIBITOR; P34(CDC2) KINASE; CARCINOMA-CELLS; P34CDC2; PHOSPHORYLATION; OLOMOUCINE; 6-DIMETHYLAMINOPURINE;
Keywords:
CELL CYCLE; CYCLIN-DEPENDENT KINASE; PURINE; PROTEIN-KINASE INHIBITOR; ANTITUMOR AGENT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
53
Recensione:
Indirizzi per estratti:
Citazione:
W.F. Deazevedo et al., "INHIBITION OF CYCLIN-DEPENDENT KINASES BY PURINE ANALOGS - CRYSTAL-STRUCTURE OF HUMAN CDK2 COMPLEXED WITH ROSCOVITINE", European journal of biochemistry, 243(1-2), 1997, pp. 518-526

Abstract

Cyclin-dependent kinases (cdk) control the cell division cycle (cdc). These kinases and their regulators are frequently deregulated in human tumours. A potent inhibitor of cdks, roscovitine droxyethylamino)-6-benzylamino-9-isopropylpurine], was identified by screening a series of C2,N-6,N9-substituted adenines on purified cdc2/cyclin B. Roscovitine displays high efficiency and high selectivity (Meijer, L., Borgne, A., Mulner, O., Chong, J. P. J., Blow, J. J., Inagaki, N., Inagaki, M.,Delcros, J.-G. & Moulinoux, J.-P. (1997) Eur. J. Biochem. 243, 527-536). It behaves as a competitive inhibitor for ATP binding to cdc2. We determined the crystal structure of a complex between cdk2 and roscovitine at 0.24-nm (2.4 Angstrom) resolution and refined to an R(factor) of 0.18. The purine portion of the inhibitor binds to the adenine binding pocket of cdk2. The position of the benzyl ring group of the inhibitor enables the inhibitor to make contacts with the enzyme not observed in the ATP-complex structure. Analysis of the position of this benzyl ring explains the specificity of roscovitine in inhibiting cdk2. The structure also reveals that the (R)-stereoisomer of roscovitine is bound to cdk2. The (R)-isomer is about twice as potent in inhibiting cdc2/cyclin B than the (S)-isomer. Results from structure/activity studies and from analysis of the cdk2/roscovitine complex crystal structureshould allow the design of even more potent cdk inhibitors.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 28/11/20 alle ore 03:24:54