Human Thymidylate Synthase Is in the Closed Conformation When Complexed with dUMP and Raltitrexed, an Antifolate Drug,
- 23 January 2001
- journal article
- research article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 40 (7) , 1897-1902
- https://doi.org/10.1021/bi002413i
Abstract
Thymidylate synthase (TS) is a major target in the chemotherapy of colorectal cancer and some other neoplasms while raltitrexed (Tomudex, ZD1694) is an antifolate inhibitor of TS approved for clinical use in several European countries. The crystal structure of the complex between recombinant human TS, dUMP, and raltitrexed has been determined at 1.9 Å resolution. In contrast to the situation observed in the analogous complex of the rat TS, the enzyme is in the closed conformation and a covalent bond between the catalytic Cys 195 and dUMP is present in both subunits. This mode of ligand binding is similar to that of the analogous complex of the Escherichia coli enzyme. The only major differences observed are a direct hydrogen bond between His 196 and the O4 atom of dUMP and repositioning of the side chain of Tyr 94 by about 2 Å. The thiophene ring of the drug is disordered between two parallel positions.Keywords
This publication has 6 references indexed in Scilit:
- Crystallography & NMR System: A New Software Suite for Macromolecular Structure DeterminationActa Crystallographica Section D-Biological Crystallography, 1998
- THE CATALYTIC MECHANISM AND STRUCTURE OF THYMIDYLATE SYNTHASEAnnual Review of Biochemistry, 1995
- The CCP4 suite: programs for protein crystallographyActa Crystallographica Section D-Biological Crystallography, 1994
- AMoRe: an automated package for molecular replacementActa Crystallographica Section A Foundations of Crystallography, 1994
- MOLSCRIPT: a program to produce both detailed and schematic plots of protein structuresJournal of Applied Crystallography, 1991
- A solution for the best rotation to relate two sets of vectorsActa Crystallographica Section A, 1976