7svt

Mycobacterium tuberculosis 3-hydroxyl-ACP dehydratase HadAB in complex with 1,3-diarylpyrazolyl-acylsulfonamide inhibitor

spinqualitylabelsall models 7svt, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7svt is a 8 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Ligands: CI7, EDO, GOL, PEG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function A0A045H4M9_MYCTX Publication Abstract from PubMed Alternative mode-of-inhibition of clinically validated targets is an effective strategy for circumventing existing clinical drug resistance. Herein, we report 1,3-diarylpyrazolyl-acylsulfonamides as potent inhibitors of HadAB/BC, a 3-hydroxyl-ACP dehydratase complex required to iteratively elongate the meromycolate chain of mycolic acids in Mycobacterium tuberculosis (Mtb). Mutations in compound 1-resistant Mtb mutants mapped to HadC (Rv0637; K157R), while chemoproteomics confirmed the compound's binding to HadA (Rv0635), HadB (Rv0636), and HadC. The compounds effectively inhibited the HadAB and HadBC enzyme activities and affected mycolic acid biosynthesis in Mtb, in a concentration-dependent manner. Unlike known 3-hydroxyl-ACP dehydratase complex inhibitors of clinical significance, isoxyl and thioacetazone, 1,3-diarylpyrazolyl-acylsulfonamides did not require activation by EthA and thus are not liable to EthA-mediated resistance. Further, the crystal structure of a key compound in a complex with Mtb HadAB revealed unique binding interactions within the active site of HadAB, providing a useful tool for further structure-based optimization of the series. 1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex in Mycobacterium tuberculosis.,Singh V, Grzegorzewicz AE, Fienberg S, Muller R, Khonde LP, Sanz O, Alfonso S, Urones B, Drewes G, Bantscheff M, Ghidelli-Disse S, Ioerger TR, Angala B, Liu J, Lee RE, Sacchettini JC, Krieger IV, Jackson M, Chibale K, Ghorpade SR ACS Infect Dis. 2022 Nov 11;8(11):2315-2326. doi: 10.1021/acsinfecdis.2c00392., Epub 2022 Nov 3. PMID:36325756 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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