6S88

Fumarate hydratase of Mycobacterium tuberculosis in complex with formate and allosteric modulator N-(2-Methoxy-5-((1,2,4,5-tetrahydro-3H-benzo[d]azepin-3-yl)sulfonyl)phenyl)-2-(4-oxo-3,4-dihydrophthalazin-1-yl)acetamide

6S88 の概要

• エントリーDOI: 10.2210/pdb6s88/pdb
• 分子名称: Fumarate hydratase class II, ~{N}-[2-methoxy-5-(1,2,4,5-tetrahydro-3-benzazepin-3-ylsulfonyl)phenyl]-2-(4-oxidanylidene-3~{H}-phthalazin-1-yl)ethanamide, FORMIC ACID, ... (5 entities in total)
• 機能のキーワード: fumarate hydratase, fumarase, lyase
• 由来する生物種: Mycobacterium tuberculosis
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 201874.72

構造登録者

Whitehouse, A.J.,Libardo, M.D.,Kasbekar, M.,Brear, P.,Fischer, G.,Thomas, C.J.,Barry, C.E.,Boshoff, H.I.,Coyne, A.G.,Abell, C. (登録日: 2019-07-08, 公開日: 2019-09-25, 最終更新日: 2024-01-24)

主引用文献

Whitehouse, A.J.,Libardo, M.D.J.,Kasbekar, M.,Brear, P.D.,Fischer, G.,Thomas, C.J.,Barry 3rd, C.E.,Boshoff, H.I.M.,Coyne, A.G.,Abell, C.
Targeting of Fumarate Hydratase fromMycobacterium tuberculosisUsing Allosteric Inhibitors with a Dimeric-Binding Mode.
J.Med.Chem., 62:10586-10604, 2019

PubMed Abstract: With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in (), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a high-throughput screening hit that binds in a nonconserved allosteric site. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with sub-micromolar inhibition. Further, the screening of this series against in vitro identified compounds with potent minimum inhibitory concentrations.

PubMed: 31517489
DOI: 10.1021/acs.jmedchem.9b01203

実験手法

X-RAY DIFFRACTION (1.59 Å)