5IWC

Mycobacterium tuberculosis CysM in complex with the Urea-scaffold inhibitor 3 [4-(3-([1,1'-Biphenyl]-3-yl)ureido)-2-hydroxybenzoic acid]

5IWC の概要

• エントリーDOI: 10.2210/pdb5iwc/pdb
• 関連するPDBエントリー: 3DKI 3FGP
• 分子名称: O-phosphoserine sulfhydrylase, PYRIDOXAL-5'-PHOSPHATE, 4-{[([1,1'-biphenyl]-3-yl)carbamoyl]amino}-2-hydroxybenzoic acid, ... (4 entities in total)
• 機能のキーワード: mycobacterium tuberculosis, cysteine biosynthesis, sulphur metabolism, inhibitor, lyase, transferase
• 由来する生物種: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 70639.22

構造登録者

Schnell, R.,Maric, S.,Lindqvist, Y.,Schneider, G. (登録日: 2016-03-22, 公開日: 2016-08-17, 最終更新日: 2024-01-10)

主引用文献

Brunner, K.,Maric, S.,Reshma, R.S.,Almqvist, H.,Seashore-Ludlow, B.,Gustavsson, A.L.,Poyraz, O.,Yogeeswari, P.,Lundback, T.,Vallin, M.,Sriram, D.,Schnell, R.,Schneider, G.
Inhibitors of the Cysteine Synthase CysM with Antibacterial Potency against Dormant Mycobacterium tuberculosis.
J.Med.Chem., 59:6848-6859, 2016

PubMed Abstract: Cysteine is an important amino acid in the redox defense of Mycobacterium tuberculosis, primarily as a building block of mycothiol. Genetic studies have implicated de novo cysteine biosynthesis in pathogen survival in infected macrophages, in particular for persistent M. tuberculosis. Here, we report on the identification and characterization of potent inhibitors of CysM, a critical enzyme in cysteine biosynthesis during dormancy. A screening campaign of 17 312 compounds identified ligands that bind to the active site with micromolar affinity. These were characterized in terms of their inhibitory potencies and structure-activity relationships through hit expansion guided by three-dimensional structures of enzyme-inhibitor complexes. The top compound binds to CysM with 300 nM affinity and displays selectivity over the mycobacterial homologues CysK1 and CysK2. Notably, two inhibitors show significant potency in a nutrient-starvation model of dormancy of Mycobacterium tuberculosis, with little or no cytotoxicity toward mammalian cells.

PubMed: 27379713
DOI: 10.1021/acs.jmedchem.6b00674

実験手法

X-RAY DIFFRACTION (2.7 Å)