7l6c
From Proteopedia
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==Crystal Structure of Enoyl-[acyl-carrier-protein] reductase InhA from Mycobacterium abscessus in complex with NAD== | ==Crystal Structure of Enoyl-[acyl-carrier-protein] reductase InhA from Mycobacterium abscessus in complex with NAD== | ||
| - | <StructureSection load='7l6c' size='340' side='right'caption='[[7l6c]]' scene=''> | + | <StructureSection load='7l6c' size='340' side='right'caption='[[7l6c]], [[Resolution|resolution]] 1.85Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7L6C OCA]. For a <b>guided tour on the structure components</b> use [ | + | <table><tr><td colspan='2'>[[7l6c]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacteroides_abscessus_ATCC_19977 Mycobacteroides abscessus ATCC 19977]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7L6C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7L6C FirstGlance]. <br> |
| - | </td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr> |
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7l6c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7l6c OCA], [https://pdbe.org/7l6c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7l6c RCSB], [https://www.ebi.ac.uk/pdbsum/7l6c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7l6c ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/B1MC30_MYCA9 B1MC30_MYCA9] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | There is an unmet medical need for effective treatments against Mycobacterium abscessus pulmonary infections, to which cystic fibrosis (CF) patients are particularly vulnerable. Recent studies showed that the antitubercular drug isoniazid is inactive against M. abscessus due to the incapacity of the catalase-peroxidase to convert the pro-drug into a reactive metabolite that inhibits the enoyl-ACP reductase InhA. To validate InhAMAB as a druggable target in M. abscessus, we assayed the activity of NITD-916, a 4-hydroxy-2-pyridone lead candidate initially described as a direct inhibitor of InhA that bypasses KatG bioactivation in Mycobacterium tuberculosis. The compound displayed low MIC values against rough and smooth clinical isolates in vitro and significantly reduced the bacterial burden inside human macrophages. Moreover, treatment with NITD-916 reduced the number and size of intracellular mycobacterial cords, regarded as markers of the severity of the infection. Importantly, NITD-916 significantly lowered the M. abscessus burden in CF-derived lung airway organoids. From a mechanistic perspective, NITD-916 abrogated de novo synthesis of mycolic acids and NITD-916-resistant spontaneous mutants harbored point mutations in InhAMAB at residue 96. That NITD-916 targets InhAMAB directly without activation requirements was confirmed genetically and by resolving the crystal structure of the protein in complex with NADH and NITD-916. These findings collectively indicate that InhAMAB is an attractive target to be exploited for future chemotherapeutic developments against this difficult-to-treat mycobacterium and highlight the potential of NITD-916 derivatives for further evaluation in preclinical settings. | ||
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| + | Efficacy and Mode of Action of a Direct Inhibitor of Mycobacterium abscessus InhA.,Alcaraz M, Roquet-Baneres F, Leon-Icaza SA, Abendroth J, Boudehen YM, Cougoule C, Edwards TE, Kremer L ACS Infect Dis. 2022 Sep 15. doi: 10.1021/acsinfecdis.2c00314. PMID:36107992<ref>PMID:36107992</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7l6c" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| + | [[Category: Mycobacteroides abscessus ATCC 19977]] | ||
Revision as of 06:22, 26 October 2022
Crystal Structure of Enoyl-[acyl-carrier-protein] reductase InhA from Mycobacterium abscessus in complex with NAD
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