Biomedicine

Refining a Drug

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Science  27 Apr 2001:
Vol. 292, Issue 5517, pp. 605
DOI: 10.1126/science.292.5517.605a

Taxol is an antitumor drug that binds to and stabilizes microtubules. Its binding site has been located on the β-subunit of the αβ tubulin dimer by electron crystallography; however, its precise conformation could not be resolved.

Snyder et al. have docked many different taxol conformers, derived from various structural studies, into the β-tubulin structure; three similar conformers gave reasonable fits, and one of these was refined to give a T-shaped taxol molecule. Whereas previous models have predicted that the hydrophobic moieties of taxol would associate with each other, in this model these groups interact with hydrophobic parts of the protein. Taxol binding converts a hydrophobic cleft in β-tubulin into a hydrophilic surface, and as such is functionally reminiscent of a peptide loop seen in α-tubulin. The lateral packing of these surfaces in the tubulin dimer may explain how taxol increases microtubule stability. The model rationalizes the taxol resistance conferred by some tubulin mutations and also is consistent with photoaffinity labeling studies and with structure-activity data obtained using synthetically substituted taxols. — VV

Proc. Natl. Acad. Sci. U.S.A.98, 5312 (2001).

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