7svt

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'''Unreleased structure'''
 
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The entry 7svt is ON HOLD until Paper Publication
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==Mycobacterium tuberculosis 3-hydroxyl-ACP dehydratase HadAB in complex with 1,3-diarylpyrazolyl-acylsulfonamide inhibitor==
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<StructureSection load='7svt' size='340' side='right'caption='[[7svt]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[7svt]] is a 8 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7SVT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7SVT FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CI7:3-[1-(4-bromophenyl)-3-(4-chlorophenyl)-1H-pyrazol-4-yl]-N-(methanesulfonyl)propanamide'>CI7</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7svt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7svt OCA], [https://pdbe.org/7svt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7svt RCSB], [https://www.ebi.ac.uk/pdbsum/7svt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7svt ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/A0A045H4M9_MYCTX A0A045H4M9_MYCTX]
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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Authors: Krieger, I.V., Sacchettini, J.C., TB Structural Genomics Consortium (TBSGC)
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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<ref>PMID:36325756</ref>
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Description: Mycobacterium tuberculosis 3-hydroxyl-ACP dehydratase HadAB in complex with 1,3-diarylpyrazolyl-acylsulfonamide inhibitor
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Krieger, I.V]]
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<div class="pdbe-citations 7svt" style="background-color:#fffaf0;"></div>
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[[Category: Sacchettini, J.C]]
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== References ==
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[[Category: Tb Structural Genomics Consortium (Tbsgc)]]
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Large Structures]]
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[[Category: Mycobacterium tuberculosis]]
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[[Category: Krieger IV]]
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[[Category: Sacchettini JC]]

Revision as of 20:04, 16 November 2022

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

PDB ID 7svt

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