Ligand-induced distortion of an active site in thymidylate synthase upon binding anticancer drug 1843u89

Andrzej Weichsel, William R. Montfort

Research output: Contribution to journalArticle

34 Scopus citations

Abstract

The anticancer drug 1843U89 inhibits thymidylate synthase (TS) at sub-nanomolar concentrations and is undergoing clinical trial. The 1.95 Â 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 theTS 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.

Original languageEnglish (US)
Pages (from-to)1095-1101
Number of pages7
JournalNature Structural Biology
Volume2
Issue number12
DOIs
StatePublished - Dec 1995

ASJC Scopus subject areas

  • Structural Biology
  • Biochemistry
  • Genetics

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