8HFM
Crystal Structure of Mycobacterium smegmatis MshC
Summary for 8HFM
| Entry DOI | 10.2210/pdb8hfm/pdb |
| Descriptor | L-cysteine:1D-myo-inositol 2-amino-2-deoxy-alpha-D-glucopyranoside ligase, CALCIUM ION, ZINC ION, ... (4 entities in total) |
| Functional Keywords | rossmann fold, ligase |
| Biological source | Mycolicibacterium smegmatis |
| Total number of polymer chains | 1 |
| Total formula weight | 45614.09 |
| Authors | Pang, L.,Weeks, S.D.,Strelkov, S.V. (deposition date: 2022-11-11, release date: 2022-12-07, Last modification date: 2023-10-25) |
| Primary citation | 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 Cited by 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: 36499418DOI: 10.3390/ijms232315095 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.41 Å) |
Structure validation
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