Ligand-induced distortion of an active site in thymidylate synthase upon binding anticancerdrug 1843U89
- 1 December 1995
- journal article
- Published by Springer Nature in Nature Structural & Molecular Biology
- Vol. 2 (12) , 1095-1101
- https://doi.org/10.1038/nsb1295-1095
Abstract
The anticancer drug 1843U89 inhibits thymidylate synthase (TS) at sub-nanomolar concentrations and is undergoing clinical trial. The 1.95 A 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.Keywords
This publication has 27 references indexed in Scilit:
- Promotion of purine nucleotide binding to thymidylate synthase by a potent folate analogue inhibitor, 1843U89.Proceedings of the National Academy of Sciences, 1995
- Water-mediated substrate/product discrimination: The product complex of thymidylate synthase at 1.83 .ANG.Biochemistry, 1994
- Stereochemical mechanism of action for thymidylate synthase based on the X-ray structure of the covalent inhibitory ternary complex with 5-fluoro-2′-deoxyuridylate and 5,10-methylenetetrahydrofolateJournal of Molecular Biology, 1990
- Crystal structure of Escherichia coli thymidylate synthase containing bound 5-fluoro-2′-deoxyuridylate and 10-propargyl-5,8-dideazafolateJournal of Molecular Biology, 1990
- Pairwise specificity and sequential binding in enzyme catalysis: thymidylate synthaseBiochemistry, 1990
- Structure, multiple site binding, and segmental accommodation in thymidylate synthase on binding dUMP and an anti-folateBiochemistry, 1990
- Plastic adaptation toward mutations in proteins: Structural comparison of thymidylate synthasesProteins-Structure Function and Bioinformatics, 1990
- The clinical pharmacokinetics of the novel antifolate N10-propargyl-5,8-dideazafolic acid (CB 3717)Cancer Chemotherapy and Pharmacology, 1985
- Studies on identifying the folylpolyglutamate binding sites of Lactobacillus casei thymidylate synthetaseArchives of Biochemistry and Biophysics, 1982
- A potent antitumour quinazoline inhibitor of thymidylate synthetase: Synthesis, biological properties and therapeutic results in micePublished by Elsevier ,1981