Structural Basis for Inhibition of the Hsp90 Molecular Chaperone by the Antitumor Antibiotics Radicicol and Geldanamycin

The cellular activity of several regulatory and signal transduction proteins, which depend on the Hsp90 molecular chaperone for folding, is markedly decreased by geldanamycin and by radicicol (monorden). We now show that these unrelated compounds both bind to the N-terminal ATP/ADP-binding domain of...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1999-01, Vol.42 (2), p.260-266
Main Authors: Roe, S. Mark, Prodromou, Chrisostomos, O'Brien, Ronan, Ladbury, John E, Piper, Peter W, Pearl, Laurence H
Format: Article
Language:English
Subjects:
Adenosine Diphosphate - chemistry
Adenosine Triphosphatases - antagonists & inhibitors
Antibiotics, Antineoplastic - chemistry
Antibiotics, Antineoplastic - metabolism
Antibiotics, Antineoplastic - pharmacology
Antineoplastic agents
Benzoquinones
Biological and medical sciences
Calorimetry
Crystallography, X-Ray
General aspects
HSP90 Heat-Shock Proteins - antagonists & inhibitors
HSP90 Heat-Shock Proteins - metabolism
Lactams, Macrocyclic
Lactones - chemistry
Lactones - metabolism
Lactones - pharmacology
Macrolides
Medical sciences
Models, Molecular
Molecular Mimicry
Pharmacology. Drug treatments
Quinones - chemistry
Quinones - metabolism
Quinones - pharmacology
Structure-Activity Relationship
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Summary:The cellular activity of several regulatory and signal transduction proteins, which depend on the Hsp90 molecular chaperone for folding, is markedly decreased by geldanamycin and by radicicol (monorden). We now show that these unrelated compounds both bind to the N-terminal ATP/ADP-binding domain of Hsp90, with radicicol displaying nanomolar affinity, and both inhibit the inherent ATPase activity of Hsp90 which is essential for its function in vivo. Crystal structure determinations of Hsp90 N-terminal domain complexes with geldanamycin and radicicol identify key aspects of their nucleotide mimicry and suggest a rational basis for the design of novel antichaperone drugs.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm980403y