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Ligand-induced distortion of an active site in thymidylate synthase upon binding anticancerdrug 1843U89

Nature Structural Biology volume 2, pages 1095–1101 (1995)Cite this article

Abstract

The anticancer drug 1843U89 inhibits thymidylate synthase (TS) at sub-nanomolar concentrations and is undergoing clinical trial. The 1.95 Å crystal structure of Escherichia coli TS bound to the drug and dUMP reveals that the 1843U89 binding surface includes a hydrophobic patch that is normally buried. To reach this patch, 1843U89 inserts into the wall of the TS active site, resulting in a severe local distortion of the protein. In this new conformation, active-site groups that normally bind to the catalytic cofactor methylene-tetrahydrofolate instead bind to 1843U89 in new ways. This structure provides a rare example of a protein that can bind tightly to distinct substances using a single, flexible, binding surface. This has implications for drug design, as 1843U89 could not have been obtained from current structure-based approaches.

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  1. Department of Biochemistry, University of Arizona, Tucson, Arizona, 85721, USA

    Andrzej Weichsel & William R. Montfort

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  2. William R. Montfort
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Weichsel, A., Montfort, W. Ligand-induced distortion of an active site in thymidylate synthase upon binding anticancerdrug 1843U89. Nat Struct Mol Biol 2, 1095–1101 (1995). https://doi.org/10.1038/nsb1295-1095

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