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Science 6 August 2004:
Vol. 305. no. 5685, pp. 866 - 869
DOI: 10.1126/science.1099190
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Reports

The Binding Mode of Epothilone A on {alpha},ß-Tubulin by Electron Crystallography

James H. Nettles,1 Huilin Li,2 Ben Cornett,3 Joseph M. Krahn,4 James P. Snyder,3* Kenneth H. Downing5*

The structure of epothilone A, bound to {alpha},ß-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.

1 Molecular and Systems Pharmacology, Emory University, Atlanta, GA 30322, USA.
2 Department of Biology, Brookhaven National Laboratory, Upton, NY 11973, USA.
3 Department of Chemistry, Emory University, Atlanta, GA 30322, USA.
4 Laboratory of Structural Biology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
5 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA.

* To whom correspondence should be addressed. E-mail: snyder{at}euch4e.chem.emory.edu (J.P.S.); khdowning{at}lbl.gov (K.H.D.)

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