Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug

Thymidylate synthase (TS) is a major target in the chemotherapy of colorect al cancer and some other neoplasms while raltitrexed (Tomudex, ZD1694) is a n antifolate inhibitor of TS approved for clinical use in several European countries. The crystal structure of the complex between recombinant human T S, dUMP, and raltitrexed has been determined at 1.9 A resolution. In contra st to the situation observed in the analogous complex of the rat TS, the en zyme is in the closed conformation and a covalent bond between the catalyti c 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 Hi s 196 and the O4 atom of dUMP and repositioning of the side chain of Tyr 94 by about 2 A. The thiophene ring of the drug is disordered between two par allel positions.