3NJ8

Crystal structure of T. gondii enoyl acyl carrier protein reductase with bound triclosan like inhibitor

3NJ8 の概要

• エントリーDOI: 10.2210/pdb3nj8/pdb
• 関連するPDBエントリー: 2O2S 2O2Y 2O50
• 分子名称: Enoyl-acyl carrier reductase, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, 3-chloro-4-(2-hydroxy-4-propylphenoxy)benzonitrile, ... (4 entities in total)
• 機能のキーワード: enoyl reductase, enr triclosan, rossmann nad binding fold, nadh binding, oxidoreductase
• 由来する生物種: Toxoplasma gondii
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 68685.44

構造登録者

Muench, S.P.,Ruzheinikov, S.N.,Rice, D.W. (登録日: 2010-06-17, 公開日: 2010-09-29, 最終更新日: 2024-02-21)

主引用文献

Tipparaju, S.K.,Muench, S.P.,Mui, E.J.,Ruzheinikov, S.N.,Lu, J.Z.,Hutson, S.L.,Kirisits, M.J.,Prigge, S.T.,Roberts, C.W.,Henriquez, F.L.,Kozikowski, A.P.,Rice, D.W.,McLeod, R.L.
Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase.
J.Med.Chem., 53:6287-6300, 2010

PubMed Abstract: Toxoplasmosis causes significant morbidity and mortality, and yet available medicines are limited by toxicities and hypersensitivity. Because improved medicines are needed urgently, rational approaches were used to identify novel lead compounds effective against Toxoplasma gondii enoyl reductase (TgENR), a type II fatty acid synthase enzyme essential in parasites but not present in animals. Fifty-three compounds, including three classes that inhibit ENRs, were tested. Six compounds have antiparasite MIC(90)s < or = 6 microM without toxicity to host cells, three compounds have IC(90)s < 45 nM against recombinant TgENR, and two protect mice. To further understand the mode of inhibition, the cocrystal structure of one of the most promising candidate compounds in complex with TgENR has been determined to 2.7 A. The crystal structure reveals that the aliphatic side chain of compound 19 occupies, as predicted, space made available by replacement of a bulky hydrophobic residue in homologous bacterial ENRs by Ala in TgENR. This provides a paradigm, conceptual foundation, reagents, and lead compounds for future rational development and discovery of improved inhibitors of T. gondii.

PubMed: 20698542
DOI: 10.1021/jm9017724

実験手法

X-RAY DIFFRACTION (2.7 Å)