4r9r
From Proteopedia
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| - | ''' | + | ==Mycobacterium tuberculosis InhA bound to NITD-564== |
| + | <StructureSection load='4r9r' size='340' side='right' caption='[[4r9r]], [[Resolution|resolution]] 2.90Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[4r9r]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4R9R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4R9R FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=3KX:6-(CYCLOHEXYLMETHYL)-4-HYDROXY-3-PHENYLPYRIDIN-2(1H)-ONE'>3KX</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr> | ||
| + | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4r9s|4r9s]]</td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Enoyl-[acyl-carrier-protein]_reductase_(NADH) Enoyl-[acyl-carrier-protein] reductase (NADH)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.3.1.9 1.3.1.9] </span></td></tr> | ||
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4r9r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4r9r OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4r9r RCSB], [http://www.ebi.ac.uk/pdbsum/4r9r PDBsum]</span></td></tr> | ||
| + | </table> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase InhA is one of the few clinically validated targets in tuberculosis drug discovery. We report the identification of a new class of direct InhA inhibitors, the 4-hydroxy-2-pyridones, using phenotypic high-throughput whole-cell screening. This class of orally active compounds showed potent bactericidal activity against common isoniazid-resistant TB clinical isolates. Biophysical studies revealed that 4-hydroxy-2-pyridones bound specifically to InhA in an NADH (reduced form of nicotinamide adenine dinucleotide)-dependent manner and blocked the enoyl substrate-binding pocket. The lead compound NITD-916 directly blocked InhA in a dose-dependent manner and showed in vivo efficacy in acute and established mouse models of Mycobacterium tuberculosis infection. Collectively, our structural and biochemical data open up new avenues for rational structure-guided optimization of the 4-hydroxy-2-pyridone class of compounds for the treatment of MDR-TB. | ||
| - | + | Direct inhibitors of InhA are active against Mycobacterium tuberculosis.,Manjunatha UH, S Rao SP, Kondreddi RR, Noble CG, Camacho LR, Tan BH, Ng SH, Ng PS, Ma NL, Lakshminarayana SB, Herve M, Barnes SW, Yu W, Kuhen K, Blasco F, Beer D, Walker JR, Tonge PJ, Glynne R, Smith PW, Diagana TT Sci Transl Med. 2015 Jan 7;7(269):269ra3. doi: 10.1126/scitranslmed.3010597. PMID:25568071<ref>PMID:25568071</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | == References == | |
| - | [[Category: | + | <references/> |
| - | [[Category: | + | __TOC__ |
| + | </StructureSection> | ||
| + | [[Category: Noble, C G]] | ||
| + | [[Category: Enoyl-acyl carrier protein reductase]] | ||
| + | [[Category: Oxidoreductase]] | ||
Revision as of 16:48, 21 January 2015
Mycobacterium tuberculosis InhA bound to NITD-564
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