Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent Journal Article
| Authors: | Stebbins, C. E.; Russo, A. A.; Schneider, C.; Rosen, N.; Hartl, F. U.; Pavletich, N. P. |
| Article Title: | Crystal structure of an Hsp90-geldanamycin complex: Targeting of a protein chaperone by an antitumor agent |
| Abstract: | 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 anti-tumor 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 Å 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. |
| Keywords: | nonhuman; antineoplastic agent; protein conformation; protein domain; animals; protein binding; antineoplastic activity; amino acid sequence; conserved sequence; molecular sequence data; sequence alignment; eukaryota; heat shock protein 90; hsp90 heat-shock proteins; quinones; crystal structure; models, molecular; crystallography, x-ray; cattle; conformational transition; antibiotics, antineoplastic; drug protein binding; benzoquinones; lactams, macrocyclic; geldanamycin; chaperone; humans; priority journal; article |
| Journal Title: | Cell |
| Volume: | 89 |
| Issue: | 2 |
| ISSN: | 0092-8674 |
| Publisher: | Cell Press |
| Date Published: | 1997-04-18 |
| Start Page: | 239 |
| End Page: | 250 |
| Language: | English |
| PUBMED: | 9108479 |
| PROVIDER: | scopus |
| DOI: | 10.1016/S0092-8674(00)80203-2 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 17 March 2017 -- Source: Scopus |
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