Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Diphosphate / chemistry
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Adenosine Triphosphatases / antagonists & inhibitors
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Antibiotics, Antineoplastic / chemistry
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Antibiotics, Antineoplastic / metabolism
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Antibiotics, Antineoplastic / pharmacology*
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Benzoquinones
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Calorimetry
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Crystallography, X-Ray
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / metabolism
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Lactams, Macrocyclic
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Lactones / chemistry
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Lactones / metabolism
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Lactones / pharmacology*
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Macrolides
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Models, Molecular
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Molecular Mimicry
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Quinones / chemistry
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Quinones / metabolism
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Quinones / pharmacology*
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Structure-Activity Relationship
Substances
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Antibiotics, Antineoplastic
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Benzoquinones
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HSP90 Heat-Shock Proteins
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Lactams, Macrocyclic
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Lactones
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Macrolides
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Quinones
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Adenosine Diphosphate
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Adenosine Triphosphatases
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monorden
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geldanamycin