| Antibiotic radicicol binds to the N-terminal domain of Hsp90 and shares important biologic activities with geldanamycin. | |
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MedLine Citation:
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PMID: 9672245 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The molecular chaperone Hsp90 plays an essential role in the folding and function of important cellular proteins including steroid hormone receptors, protein kinases and proteins controlling the cell cycle and apoptosis. A 15 A deep pocket region in the N-terminal domain of Hsp90 serves as an ATP/ADP-binding site and has also been shown to bind geldanamycin, the only specific inhibitor of Hsp90 function described to date. We now show that radicicol, a macrocyclic antifungal structurally unrelated to geldanamycin, also specifically binds to Hsp90. Moreover, radicicol competes with geldanamycin for binding to the N-terminal domain of the chaperone, expressed either by in vitro translation or as a purified protein, suggesting that radicicol shares the geldanamycin binding site. Radicicol, as does geldanamycin, also inhibits the binding of the accessory protein p23 to Hsp90, and interferes with assembly of the mature progesterone receptor complex. Radicicol does not deplete cells of Hsp90, but rather increases synthesis as well as the steady-state level of this protein, similar to a stress response. Finally, radicicol depletes SKBR3 cells of p185erbB2, Raf-1 and mutant p53, similar to geldanamycin. Radicicol thus represents a structurally unique antibiotic, and the first non-benzoquinone ansamycin, capable of binding to Hsp90 and interfering with its function. |
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Authors:
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T W Schulte; S Akinaga; S Soga; W Sullivan; B Stensgard; D Toft; L M Neckers |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Cell stress & chaperones Volume: 3 ISSN: 1355-8145 ISO Abbreviation: Cell Stress Chaperones Publication Date: 1998 Jun |
Date Detail:
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Created Date: 1998-09-29 Completed Date: 1998-09-29 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 9610925 Medline TA: Cell Stress Chaperones Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 100-8 Citation Subset: IM |
Affiliation:
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Medicine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. tschulte@helix.nih.gov |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibiotics, Antineoplastic / pharmacokinetics* Antifungal Agents / pharmacokinetics* Benzoquinones Binding Sites Binding, Competitive Breast Neoplasms Cell Division / drug effects Chickens Chromatography, Affinity Female HSP90 Heat-Shock Proteins / chemistry*, metabolism* Humans Lactams, Macrocyclic Lactones / pharmacokinetics*, pharmacology* Macrolides Molecular Structure Quinones / pharmacokinetics*, pharmacology Tumor Cells, Cultured |
| Chemical | |
Reg. No./Substance:
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0/Antibiotics, Antineoplastic; 0/Antifungal Agents; 0/Benzoquinones; 0/HSP90 Heat-Shock Proteins; 0/Lactams, Macrocyclic; 0/Lactones; 0/Macrolides; 0/Quinones; 12772-57-5/monorden; 30562-34-6/geldanamycin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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