1tsd
THYMIDYLATE SYNTHASE COMPLEX WITH 2'-DEOXYURIDINE 5'-MONOPHOSPHATE (DUMP) AND FOLATE ANALOG 1843U89
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OverviewOverview
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.
About this StructureAbout this Structure
1TSD is a Single protein structure of sequence from Escherichia coli with BME, UMP and F89 as ligands. Active as Thymidylate synthase, with EC number 2.1.1.45 Full crystallographic information is available from OCA.
ReferenceReference
Ligand-induced distortion of an active site in thymidylate synthase upon binding anticancer drug 1843U89., Weichsel A, Montfort WR, Nat Struct Biol. 1995 Dec;2(12):1095-101. PMID:8846221
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