The binding mode of epothilone A on alpha,beta-tubulin by electron crystallography
James H Nettles1, Huilin Li, Ben Cornett
1Molecular and Systems Pharmacology, Emory University, Atlanta, GA 30322, USA.
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.
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