5M4Z

Crystal structure of the complex of T.spiralis thymidylate synthase with N(4)-hydroxy-2'-deoxycytidine-5'-monophosphate, crystallized in the presence of N(5,10)-methylenetetrahydrofolate

5M4Z の概要

• エントリーDOI: 10.2210/pdb5m4z/pdb
• 分子名称: Thymidylate synthase, [(2~{R},3~{S},5~{R})-5-[(4~{E})-4-hydroxyimino-2-oxidanylidene-1,3-diazinan-1-yl]-3-oxidanyl-oxolan-2-yl]methyl dihydrogen phosphate, GLYCEROL, ... (4 entities in total)
• 機能のキーワード: enzyme-inhibitor complex, high-resolution structure, anticancer target, transferase
• 由来する生物種: Trichinella spiralis (Trichina worm)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 75591.64

構造登録者

Wilk, P.,Maj, P.,Jarmula, A.,Dowiercial, A.,Rode, W. (登録日: 2016-10-19, 公開日: 2017-12-20, 最終更新日: 2024-11-06)

主引用文献

Maj, P.,Jarmula, A.,Wilk, P.,Prokopowicz, M.,Rypniewski, W.,Zielinski, Z.,Dowiercial, A.,Bzowska, A.,Rode, W.
Molecular Mechanism of Thymidylate Synthase Inhibition by N 4 -Hydroxy-dCMP in View of Spectrophotometric and Crystallographic Studies.
Int J Mol Sci, 22:-, 2021

PubMed Abstract: Novel evidence is presented allowing further clarification of the mechanism of the slow-binding thymidylate synthase (TS) inhibition by N-hydroxy-dCMP (N-OH-dCMP). Spectrophotometric monitoring documented time- and temperature-, and N-OH-dCMP-dependent TS-catalyzed dihydrofolate production, accompanying the mouse enzyme incubation with N-OH-dCMP and N-methylenetetrahydrofolate, known to inactivate the enzyme by the covalent binding of the inhibitor, suggesting the demonstrated reaction to be uncoupled from the pyrimidine C(5) methylation. The latter was in accord with the hypothesis based on the previously presented structure of mouse TS (cf. PDB ID: 4EZ8), and with conclusions based on the present structure of the parasitic nematode , both co-crystallized with N-OH-dCMP and N-methylenetetrahdrofolate. The crystal structure of the mouse TS-N-OH-dCMP complex soaked with N-methylenetetrahydrofolate revealed the reaction to run via a unique imidazolidine ring opening, leaving the one-carbon group bound to the N(10) atom, thus too distant from the pyrimidine C(5) atom to enable the electrophilic attack and methylene group transfer.

PubMed: 33946210
DOI: 10.3390/ijms22094758

実験手法

X-RAY DIFFRACTION (1.179 Å)