4BQR

Mtb InhA complex with Methyl-thiazole compound 11

4BQR の概要

• エントリーDOI: 10.2210/pdb4bqr/pdb
• 関連するPDBエントリー: 4BQP
• 分子名称: ENOYL-[ACYL-CARRIER-PROTEIN] REDUCTASE [NADH], NICOTINAMIDE-ADENINE-DINUCLEOTIDE, (NZ)-2-[2,6-bis(fluoranyl)phenyl]-N-[5-[(1S)-1-(4-methyl-1,3-thiazol-2-yl)-1-oxidanyl-ethyl]-3H-1,3,4-thiadiazol-2-ylidene]ethanamide, ... (4 entities in total)
• 機能のキーワード: oxidoreductase, methyl-thiazole
• 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: 118458.56

構造登録者

Read, J.A.,Gingell, H.,Madhavapeddi, P.,Shirude, P.S. (登録日: 2013-05-31, 公開日: 2013-12-11, 最終更新日: 2024-05-08)

主引用文献

Shirude, P.S.,Madhavapeddi, P.,Naik, M.,Murugan, K.,Shinde, V.,Nandishaiah, R.,Bhat, J.,Kumar, A.,Hameed, S.,Holdgate, G.,Davies, G.,Mcmiken, H.,Hegde, N.,Ambady, A.,Venkatraman, J.,Panda, M.,Bandodkar, B.,Sambandamurthy, V.K.,Read, J.A.
Methyl-Thiazoles: A Novel Mode of Inhibition with the Potential to Develop Novel Inhibitors Targeting Inha in Mycobacterium Tuberculosis.
J.Med.Chem., 56:8533-, 2013

PubMed Abstract: InhA is a well validated Mycobacterium tuberculosis (Mtb) target as evidenced by the clinical success of isoniazid. Translating enzyme inhibition to bacterial cidality by targeting the fatty acid substrate site of InhA remains a daunting challenge. The recent disclosure of a methyl-thiazole series demonstrates that bacterial cidality can be achieved with potent enzyme inhibition and appropriate physicochemical properties. In this study, we report the molecular mode of action of a lead methyl-thiazole, along with analogues with improved CYP inhibition profile. We have identified a novel mechanism of InhA inhibition characterized by a hitherto unreported "Y158-out" inhibitor-bound conformation of the protein that accommodates a neutrally charged "warhead". An additional novel hydrophilic interaction with protein residue M98 allows the incorporation of favorable physicochemical properties for cellular activity. Notably, the methyl-thiazole prefers the NADH-bound form of the enzyme with a Kd of ~13.7 nM, as against the NAD(+)-bound form of the enzyme.

PubMed: 24107081
DOI: 10.1021/JM4012033

実験手法

X-RAY DIFFRACTION (2.05 Å)