4BQR
Mtb InhA complex with Methyl-thiazole compound 11
Summary for 4BQR
| Entry DOI | 10.2210/pdb4bqr/pdb |
| Related | 4BQP |
| Descriptor | 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) |
| Functional Keywords | oxidoreductase, methyl-thiazole |
| Biological source | MYCOBACTERIUM TUBERCULOSIS |
| Total number of polymer chains | 4 |
| Total formula weight | 118458.56 |
| Authors | Read, J.A.,Gingell, H.,Madhavapeddi, P.,Shirude, P.S. (deposition date: 2013-05-31, release date: 2013-12-11, Last modification date: 2024-05-08) |
| Primary citation | 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 Cited by 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: 24107081DOI: 10.1021/JM4012033 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.05 Å) |
Structure validation
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