Structural basis of cysteine ligase MshC inhibition by cysteinyl-sulfonamides
| Autor: | Luping Pang, Stijn Lenders, Evgenii M. Osipov, Stephen D. Weeks, Jef Rozenski, Tatiana Piller, Davie Cappoen, Sergei V. Strelkov, Arthur Van Aerschot |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
EXPRESSION
Biochemistry & Molecular Biology Chemistry Multidisciplinary Mycobacterium smegmatis PROTEIN TRANSFER-RNA SYNTHETASE Catalysis Inorganic Chemistry Ligases MYCOTHIOL Bacterial Proteins Cysteine Melanocyte-Stimulating Hormones Physical and Theoretical Chemistry MshC Molecular Biology enzyme inhibition Biology Spectroscopy Sulfonamides Science & Technology structure-activity relationship Organic Chemistry bi-substrate competitive inhibitors protein-ligand co-crystal structures Mycobacterium tuberculosis Glycopeptides General Medicine Computer Science Applications ENZYME MSHC Chemistry Physical Sciences GROWTH MYCOBACTERIUM-TUBERCULOSIS Life Sciences & Biomedicine Inositol |
| Zdroj: | International journal of molecular sciences International Journal of Molecular Sciences; Volume 23; Issue 23; Pages: 15095 |
| ISSN: | 1422-0067 |
| Popis: | Mycothiol (MSH), the major cellular thiol in Mycobacterium tuberculosis (Mtb), plays an essential role in the resistance of Mtb to various antibiotics and oxidative stresses. MshC catalyzes the ATP-dependent ligation of 1-O-(2-amino-2-deoxy-α-d-glucopyranosyl)-d-myo-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 EC50 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. ispartof: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES vol:23 issue:23 ispartof: location:Switzerland status: published |
| Databáze: | OpenAIRE |
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