4bqr | pdb_00004bqr

Mtb InhA complex with Methyl-thiazole compound 11

spinqualitylabelsall models 4bqr, resolution 2.05Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4bqr is a 4 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.05Å Ligands: IBH, NAD Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function INHA_MYCTU Publication Abstract from PubMed 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 approximately 13.7 nM, as against the NAD+-bound form of the enzyme. Methyl-Thiazoles: A Novel Mode of Inhibition with the Potential to Develop Novel Inhibitors Targeting InhA in Mycobacterium tuberculosis.,Shirude PS, 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 VK, Read JA J Med Chem. 2013 Oct 25. PMID:24107081 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Enoyl-Acyl-Carrier Protein Reductase 3D structures

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