1HVY

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

Summary for 1HVY

• Entry DOI: 10.2210/pdb1hvy/pdb
• Descriptor: THYMIDYLATE SYNTHASE, TOMUDEX, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, ... (5 entities in total)
• Functional Keywords: tomudex, raltitrexed, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus : P04818
• Total number of polymer chains: 4
• Total formula weight: 135827.09

Authors

Phan, J.,Koli, S.,Minor, W.,Dunlap, R.B.,Berger, S.H.,Lebioda, L. (deposition date: 2001-01-08, release date: 2001-01-31, Last modification date: 2022-04-13)

Primary citation

Phan, J.,Koli, S.,Minor, W.,Dunlap, R.B.,Berger, S.H.,Lebioda, L.
Human thymidylate synthase is in the closed conformation when complexed with dUMP and raltitrexed, an antifolate drug
Biochemistry, 40:1897-1902, 2001

PubMed 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 A 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 A. The thiophene ring of the drug is disordered between two parallel positions.

PubMed: 11329255
DOI: 10.1021/bi002413i

Experimental method

X-RAY DIFFRACTION (1.9 Å)