1I00

CRYSTAL STRUCTURE OF HUMAN THYMIDYLATE SYNTHASE, TERNARY COMPLEX WITH DUMP AND TOMUDEX

1I00 の概要

• エントリーDOI: 10.2210/pdb1i00/pdb
• 関連するPDBエントリー: 1HZW
• 分子名称: THYMIDYLATE SYNTHASE, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, TOMUDEX, ... (4 entities in total)
• 機能のキーワード: thymidylate synthase, human, ternary complex, dump, tomudex, open conformation, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Nucleus: P04818
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67911.48

構造登録者

Almog, R.A.,Waddling, C.A.,Maley, F.,Maley, G.F.,Van Roey, P. (登録日: 2001-01-27, 公開日: 2001-05-09, 最終更新日: 2023-08-09)

主引用文献

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

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: 11316879
DOI: 10.1110/ps.47601

実験手法

X-RAY DIFFRACTION (2.5 Å)