3ZEI
Structure of the Mycobacterium tuberculosis O-Acetylserine Sulfhydrylase (OASS) CysK1 in complex with a small molecule inhibitor
Summary for 3ZEI
| Entry DOI | 10.2210/pdb3zei/pdb |
| Descriptor | O-ACETYLSERINE SULFHYDRYLASE, PYRIDOXAL-5'-PHOSPHATE, 3-[(Z)-[(5Z)-5-[[2-(2-hydroxy-2-oxoethyloxy)phenyl]methylidene]-3-methyl-4-oxidanylidene-1,3-thiazolidin-2-ylidene]amino]benzoic acid, ... (5 entities in total) |
| Functional Keywords | hydrolase, inhibitor |
| Biological source | MYCOBACTERIUM TUBERCULOSIS |
| Total number of polymer chains | 1 |
| Total formula weight | 33681.52 |
| Authors | Poyraz, O.,Schnell, R.,Schneider, G. (deposition date: 2012-12-05, release date: 2013-08-07, Last modification date: 2023-12-20) |
| Primary citation | Poyraz, O.,Jeankumar, V.U.,Saxena, S.,Schnell, R.,Haraldsson, M.,Yogeeswari, P.,Sriram, D.,Schneider, G. Structure-Guided Design of Novel Thiazolidine Inhibitors of O-Acetyl Serine Sulfhydrylase from Mycobacterium Tuberculosis. J.Med.Chem., 56:6457-, 2013 Cited by PubMed Abstract: The cysteine biosynthetic pathway is absent in humans but essential in microbial pathogens, suggesting that it provides potential targets for the development of novel antibacterial compounds. CysK1 is a pyridoxalphosphate-dependent O-acetyl sulfhydrylase, which catalyzes the formation of l-cysteine from O-acetyl serine and hydrogen sulfide. Here we report nanomolar thiazolidine inhibitors of Mycobacterium tuberculosis CysK1 developed by rational inhibitor design. The thiazolidine compounds were discovered using the crystal structure of a CysK1-peptide inhibitor complex as template. Pharmacophore modeling and subsequent in vitro screening resulted in an initial hit compound 2 (IC50 of 103.8 nM), which was subsequently optimized by a combination of protein crystallography, modeling, and synthetic chemistry. Hit expansion of 2 by chemical synthesis led to improved thiazolidine inhibitors with an IC50 value of 19 nM for the best compound, a 150-fold higher potency than the natural peptide inhibitor (IC50 2.9 μM). PubMed: 23879381DOI: 10.1021/JM400710K PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
Download full validation report
