Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent

被引:1211
作者
Stebbins, CE
Russo, AA
Schneider, C
Rosen, N
Hartl, FU
Pavletich, NP
机构
[1] MEM SLOAN KETTERING CANC CTR, CELLULAR BIOCHEM & BIOPHYS PROGRAM, NEW YORK, NY 10021 USA
[2] CORNELL UNIV, GRAD SCH MED SCI, DEPT BIOCHEM & STRUCT BIOL, NEW YORK, NY 10021 USA
[3] MEM SLOAN KETTERING CANC CTR, HOWARD HUGHES MED INST, NEW YORK, NY 10021 USA
[4] MEM SLOAN KETTERING CANC CTR, CELL BIOL & GENET PROGRAM, NEW YORK, NY 10021 USA
[5] MEM SLOAN KETTERING CANC CTR, DEPT MED, NEW YORK, NY 10021 USA
基金
美国国家卫生研究院;
关键词
D O I
10.1016/S0092-8674(00)80203-2
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The Hsp90 chaperone is required for the activation of several families of eukaryotic protein kinases and nuclear hormone receptors, many of which are protooncogenic and play a prominent role in cancer. The geldanamycin antibiotic has antiproliferative and antitumor effects, as it binds to Hsp90, inhibits the Hsp90-mediated conformational maturation/refolding reaction, and results in the degradation of Hsp90 substrates. The structure of the geldanamycin-binding domain of Hsp90 (residues 9-232) reveals a pronounced pocket, 15 Angstrom deep, that is highly conserved across species. Geldanamycin binds inside this pocket, adopting a compact structure similar to that of a polypeptide chain in a turn conformation. This, and the pocket's similarity to substrate-binding sites, suggest that the pocket binds a portion of the polypeptide substrate and participates in the conformational maturation/refolding reaction.
引用
收藏
页码:239 / 250
页数:12
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