Human Thymidylate Synthase Is in the Closed Conformation When Complexed with dUMP and Raltitrexed, an Antifolate Drug
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- 作者：Jason Phan ; Sangita Koli ; Wladek Minor ; R. Bruce Dunlap ; Sondra H. Berger ; and Lukasz Lebioda
- 刊名：Biochemistry
- 出版年：2001
- 出版时间：February 20, 2001
- 年：2001
- 卷：40
- 期：7
- 页码：1897 - 1902
- 全文大小：237K
- 年卷期：v.40,no.7(February 20, 2001)
- ISSN：1520-4995
文摘
Thymidylate synthase (TS) is a major target in the chemotherapy of colorectal cancer andsome other neoplasms while raltitrexed (Tomudex, ZD1694) is an antifolate inhibitor of TS approved forclinical use in several European countries. The crystal structure of the complex between recombinanthuman TS, dUMP, and raltitrexed has been determined at 1.9 Å resolution. In contrast to the situationobserved in the analogous complex of the rat TS, the enzyme is in the closed conformation and a covalentbond between the catalytic Cys 195 and dUMP is present in both subunits. This mode of ligand bindingis similar to that of the analogous complex of the Escherichia coli enzyme. The only major differencesobserved are a direct hydrogen bond between His 196 and the O4 atom of dUMP and repositioning of theside chain of Tyr 94 by about 2 Å. The thiophene ring of the drug is disordered between two parallelpositions.