6QYA

Crystal structure of Enteroccocus faecalis thymidylate synthase (EfTS) in complex with dUMP

6QYA の概要

• エントリーDOI: 10.2210/pdb6qya/pdb
• 関連するPDBエントリー: 6QXG 6QXH 6QXS
• 分子名称: Thymidylate synthase, 2'-DEOXYURIDINE 5'-MONOPHOSPHATE, 1,2-ETHANEDIOL, ... (8 entities in total)
• 機能のキーワード: enteroccocus faecalis thymidylate synthase, efts, folate pathway, substrate, dump, transferase
• 由来する生物種: Enterococcus faecalis; 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 148297.77

構造登録者

Pozzi, C.,Mangani, M. (登録日: 2019-03-08, 公開日: 2019-04-10, 最終更新日: 2024-01-24)

主引用文献

Pozzi, C.,Ferrari, S.,Luciani, R.,Tassone, G.,Costi, M.P.,Mangani, S.
Structural Comparison ofEnterococcus faecalisand Human Thymidylate Synthase Complexes with the Substrate dUMP and Its Analogue FdUMP Provides Hints about Enzyme Conformational Variabilities.
Molecules, 24:-, 2019

PubMed Abstract: Thymidylate synthase (TS) is an enzyme of paramount importance as it provides the only de novo source of deoxy-thymidine monophosphate (dTMP). dTMP, essential for DNA synthesis, is produced by the TS-catalyzed reductive methylation of 2'-deoxyuridine-5'-monophosphate (dUMP) using N⁵,N-methylenetetrahydrofolate (mTHF) as a cofactor. TS is ubiquitous and a validated drug target. TS enzymes from different organisms differ in sequence and structure, but are all obligate homodimers. The structural and mechanistic differences between the human and bacterial enzymes are exploitable to obtain selective inhibitors of bacterial TSs that can enrich the currently available therapeutic tools against bacterial infections. is a pathogen fully dependent on TS for dTMP synthesis. In this study, we present four new crystal structures of and human TSs in complex with either the substrate dUMP or the inhibitor FdUMP. The results provide new clues about the half-site reactivity of TS and the mechanisms underlying the conformational changes occurring in the two enzymes. We also identify relevant differences in cofactor and inhibitor binding between and human TS that can guide the design of selective inhibitors against bacterial TSs.

PubMed: 30935102
DOI: 10.3390/molecules24071257

実験手法

X-RAY DIFFRACTION (1.76 Å)