1HZW
CRYSTAL STRUCTURE OF HUMAN THYMIDYLATE SYNTHASE
Summary for 1HZW
| Entry DOI | 10.2210/pdb1hzw/pdb |
| Descriptor | THYMIDYLATE SYNTHASE, PHOSPHATE ION (3 entities in total) |
| Functional Keywords | thymidylate synthase, human, uncomplexed, open conformation, delta(7-29) mutant, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 66568.08 |
| Authors | Almog, R.,Waddling, C.A.,Maley, F.,Maley, G.F.,Van Roey, P. (deposition date: 2001-01-26, release date: 2001-05-09, Last modification date: 2024-04-03) |
| Primary citation | Almog, R.,Waddling, C.A.,Maley, F.,Maley, G.F.,Van Roey, P. Crystal structure of a deletion mutant of human thymidylate synthase Delta (7-29) and its ternary complex with Tomudex and dUMP. Protein Sci., 10:988-996, 2001 Cited by PubMed Abstract: The crystal structures of a deletion mutant of human thymidylate synthase (TS) and its ternary complex with dUMP and Tomudex have been determined at 2.0 A and 2.5 A resolution, respectively. The mutant TS, which lacks 23 residues near the amino terminus, is as active as the wild-type enzyme. The ternary complex is observed in the open conformation, similar to that of the free enzyme and to that of the ternary complex of rat TS with the same ligands. This is in contrast to Escherichia coli TS, where the ternary complex with Tomudex and dUMP is observed in the closed conformation. While the ligands interact with each other in identical fashion regardless of the enzyme conformation, they are displaced by about 1.0 A away from the catalytic cysteine in the open conformation. As a result, the covalent bond between the catalytic cysteine sulfhydryl and the base of dUMP, which is the first step in the reaction mechanism of TS and is observed in all ternary complexes of the E. coli enzyme, is not formed. This displacement results from differences in the interactions between Tomudex and the protein that are caused by differences in the environment of the glutamyl tail of the Tomudex molecule. Despite the absence of the closed conformation, Tomudex inhibits human TS ten-fold more strongly than E. coli TS. These results suggest that formation of a covalent bond between the catalytic cysteine and the substrate dUMP is not required for effective inhibition of human TS by cofactor analogs and could have implications for drug design by eliminating this as a condition for lead compounds. PubMed: 11316879DOI: 10.1110/ps.47601 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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