8HFO

Crystal Structure of Mycobacterium smegmatis MshC in Complex with Compound 7d

8HFO の概要

• エントリーDOI: 10.2210/pdb8hfo/pdb
• 関連するPDBエントリー: 8HFM 8HFN
• 分子名称: L-cysteine:1D-myo-inositol 2-amino-2-deoxy-alpha-D-glucopyranoside ligase, N-[(3M)-3-(thiophen-2-yl)benzene-1-sulfonyl]-L-cysteinamide, ZINC ION, ... (5 entities in total)
• 機能のキーワード: rossmann fold, ligase, inhibitor
• 由来する生物種: Mycolicibacterium smegmatis MC2 155
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 45956.55

構造登録者

Pang, L.,Weeks, S.D.,Strelkov, S.V. (登録日: 2022-11-11, 公開日: 2022-12-07, 最終更新日: 2023-10-25)

主引用文献

Pang, L.,Lenders, S.,Osipov, E.M.,Weeks, S.D.,Rozenski, J.,Piller, T.,Cappoen, D.,Strelkov, S.V.,Van Aerschot, A.
Structural Basis of Cysteine Ligase MshC Inhibition by Cysteinyl-Sulfonamides.
Int J Mol Sci, 23:-, 2022

PubMed Abstract: Mycothiol (MSH), the major cellular thiol in (Mtb), plays an essential role in the resistance of Mtb to various antibiotics and oxidative stresses. MshC catalyzes the ATP-dependent ligation of 1--(2-amino-2-deoxy-α-d-glucopyranosyl)-d--inositol (GlcN-Ins) with l-cysteine (l-Cys) to form l-Cys-GlcN-Ins, the penultimate step in MSH biosynthesis. The inhibition of MshC is lethal to Mtb. In the present study, five new cysteinyl-sulfonamides were synthesized, and their binding affinity with MshC was evaluated using a thermal shift assay. Two of them bind the target with EC values of 219 and 231 µM. Crystal structures of full-length MshC in complex with these two compounds showed that they were bound in the catalytic site of MshC, inducing dramatic conformational changes of the catalytic site compared to the apo form. In particular, the observed closure of the KMSKS loop was not detected in the published cysteinyl-sulfamoyl adenosine-bound structure, the latter likely due to trypsin treatment. Despite the confirmed binding to MshC, the compounds did not suppress Mtb culture growth, which might be explained by the lack of adequate cellular uptake. Taken together, these novel cysteinyl-sulfonamide MshC inhibitors and newly reported full-length apo and ligand-bound MshC structures provide a promising starting point for the further development of novel anti-tubercular drugs targeting MshC.

PubMed: 36499418
DOI: 10.3390/ijms232315095

実験手法

X-RAY DIFFRACTION (2.77 Å)