7FGX

Toxoplasma gondii dihydrofolate reductase thymidylate synthase (TgDHFR-TS) complexed with P39, NADPH and dUMP

7FGX の概要

• エントリーDOI: 10.2210/pdb7fgx/pdb
• 分子名称: Bifunctional dihydrofolate reductase-thymidylate synthase, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, 6-hexyl-5-phenyl-pyrimidine-2,4-diamine, ... (5 entities in total)
• 機能のキーワード: toxoplasma gondii, dihydrofolate reductase, thymidylate synthase, antifolate, oxidoreductase
• 由来する生物種: Toxoplasma gondii
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 280666.53

構造登録者

Vanichtanankul, J.,Yoomuang, A.,Taweechai, S.,Saeyang, T.,Yuvaniyama, J.,Tarnchompoo, B.,Yuthavong, Y.,Kamchonwongpaisan, S. (登録日: 2021-07-28, 公開日: 2022-06-29, 最終更新日: 2023-11-29)

主引用文献

Vanichtanankul, J.,Yoomuang, A.,Taweechai, S.,Saeyang, T.,Pengon, J.,Yuvaniyama, J.,Tarnchompoo, B.,Yuthavong, Y.,Kamchonwongpaisan, S.
Structural Insight into Effective Inhibitors' Binding to Toxoplasma gondii Dihydrofolate Reductase Thymidylate Synthase.
Acs Chem.Biol., 17:1691-1702, 2022

PubMed Abstract: Pyrimethamine (Pyr), a known dihydrofolate reductase (DHFR) inhibitor, has long been used to treat toxoplasmosis caused by (Tg) infection. However, Pyr is effective only at high doses with associated toxicity to patients, calling for safer alternative treatments. In this study, we investigated a series of Pyr analogues, previously developed as DHFR inhibitors of bifunctional DHFR-thymidylate synthase (PfDHFR-TS), for their activity against DHFR-TS (TgDHFR-TS). Of these, a set of compounds with a substitution at the position of the pyrimidine ring exhibited high binding affinities (in a low nanomolar range) against TgDHFR-TS and inhibitory activity. Three-dimensional structures of TgDHFR-TS reported here include the ternary complexes with Pyr, P39, or P40. A comparison of these structures showed the minor steric strain between the -chlorophenyl group of Pyr and Thr83 of TgDHFR-TS. Such a conflict was relieved in the complexes with the two analogues, P39 and P40, explaining their highest binding affinities described herein. Moreover, these structures suggested that the hydrophobic environment in the active-site pocket could be used for drug design to increase the potency and selectivity of antifolate inhibitors. These findings would accelerate the development of new antifolate drugs to treat toxoplasmosis.

PubMed: 35715223
DOI: 10.1021/acschembio.1c00627

実験手法

X-RAY DIFFRACTION (2.05 Å)