Abstract
The structure of epothilone A, bound to alpha,beta-tubulin in zinc-stabilized sheets, was determined by a combination of electron crystallography at 2.89 angstrom resolution and nuclear magnetic resonance-based conformational analysis. The complex explains both the broad-based epothilone structure-activity relationship and the known mutational resistance profile. Comparison with Taxol shows that the longstanding expectation of a common pharmacophore is not met, because each ligand exploits the tubulin-binding pocket in a unique and independent manner.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Binding Sites
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Crystallography
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Crystallography, X-Ray
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Epothilones / chemistry
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Epothilones / metabolism*
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Epothilones / pharmacology
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Hydrogen Bonding
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Hydrophobic and Hydrophilic Interactions
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Ligands
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Models, Molecular
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Molecular Conformation
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Molecular Structure
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Mutation
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Nuclear Magnetic Resonance, Biomolecular
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Paclitaxel / metabolism
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Protein Conformation
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Stereoisomerism
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Structure-Activity Relationship
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Tubulin / chemistry
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Tubulin / genetics
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Tubulin / metabolism*
Substances
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Epothilones
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Ligands
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Tubulin
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epothilone A
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Paclitaxel