4O7U

Etherocomplex of Enteroccocus faecalis thymidylate synthase with 5-hydroxymethilene-6-hydrofolic acid and the phtalimidic inhibitor SS7

4O7U の概要

• エントリーDOI: 10.2210/pdb4o7u/pdb
• 関連するPDBエントリー: 3UWL
• 分子名称: Thymidylate synthase, SULFATE ION, 5-HYDROXYMETHYLENE-6-HYDROFOLIC ACID, ... (6 entities in total)
• 機能のキーワード: transferase, folate binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Enterococcus faecalis
• 細胞内の位置: Cytoplasm : Q834R3
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 146893.13

構造登録者

Mangani, S.,Pozzi, C. (登録日: 2013-12-26, 公開日: 2014-12-31, 最終更新日: 2024-02-28)

主引用文献

Catalano, A.,Luciani, R.,Carocci, A.,Cortesi, D.,Pozzi, C.,Borsari, C.,Ferrari, S.,Mangani, S.
X-ray crystal structures of Enterococcus faecalis thymidylate synthase with folate binding site inhibitors.
Eur.J.Med.Chem., 123:649-664, 2016

PubMed Abstract: Infections caused by Enterococcus faecalis (Ef) represent nowadays a relevant health problem. We selected Thymidylate synthase (TS) from this organism as a potential specific target for antibacterial therapy. We have previously demonstrated that species-specific inhibition of the protein can be achieved despite the relatively high structural similarity among bacterial TSs and human TS. We had previously obtained the EfTS crystal structure of the protein in complex with the metabolite 5-formyl-tetrahydrofolate (5-FTHF) suggesting the protein role as metabolite reservoir; however, protein-inhibitors complexes were still missing. In the present work we identified some inhibitors bearing the phthalimidic core from our in-house library and we performed crystallographic screening towards EfTS. We obtained two X-ray crystallographic structures: the first with a weak phthalimidic inhibitor bound in one subunit and 5-hydroxymethylene-6-hydrofolic acid (5-HMHF) in the other subunit; a second X-ray structure complex with methotrexate. The structural information achieved confirm the role of EfTS as an enzyme involved in the folate pool system and provide a structural basis for structure-based drug design.

PubMed: 27517810
DOI: 10.1016/j.ejmech.2016.07.066

実験手法

X-RAY DIFFRACTION (2.4 Å)