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| | ==Crystal structure of InhA bound to triclosan derivative 17== | | ==Crystal structure of InhA bound to triclosan derivative 17== |
| - | <StructureSection load='3fne' size='340' side='right' caption='[[3fne]], [[Resolution|resolution]] 1.98Å' scene=''> | + | <StructureSection load='3fne' size='340' side='right'caption='[[3fne]], [[Resolution|resolution]] 1.98Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3fne]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3FNE OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3FNE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3fne]] is a 4 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=3FNE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3FNE FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8PC:2-(2,4-DICHLOROPHENOXY)-5-(PYRIDIN-2-YLMETHYL)PHENOL'>8PC</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.98Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3fnf|3fnf]], [[3fng|3fng]], [[3fnh|3fnh]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8PC:2-(2,4-DICHLOROPHENOXY)-5-(PYRIDIN-2-YLMETHYL)PHENOL'>8PC</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">inhA, Rv1484, MT1531, MTCY277.05 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</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=3fne FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fne OCA], [https://pdbe.org/3fne PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3fne RCSB], [https://www.ebi.ac.uk/pdbsum/3fne PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3fne ProSAT]</span></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>
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| - | <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=3fne FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3fne OCA], [http://pdbe.org/3fne PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3fne RCSB], [http://www.ebi.ac.uk/pdbsum/3fne PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3fne ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/INHA_MYCTU INHA_MYCTU] |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | ==See Also== | | ==See Also== |
| | *[[Enoyl-Acyl-Carrier Protein Reductase|Enoyl-Acyl-Carrier Protein Reductase]] | | *[[Enoyl-Acyl-Carrier Protein Reductase|Enoyl-Acyl-Carrier Protein Reductase]] |
| | + | *[[Enoyl-Acyl-Carrier Protein Reductase 3D structures|Enoyl-Acyl-Carrier Protein Reductase 3D structures]] |
| | + | *[[Proteins from Mycobacterium tuberculosis|Proteins from Mycobacterium tuberculosis]] |
| | + | *[[Treatment of Tuberculosis|Treatment of Tuberculosis]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Wang, F]] | + | [[Category: Large Structures]] |
| - | [[Category: Antibiotic resistance]] | + | [[Category: Mycobacterium tuberculosis]] |
| - | [[Category: Fatty acid biosynthesis]] | + | [[Category: Wang F]] |
| - | [[Category: Inha]]
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| - | [[Category: Lipid synthesis]]
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| - | [[Category: Nad]]
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| - | [[Category: Oxidoreductase]]
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| - | [[Category: Triclosan]]
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| - | [[Category: Tuberculosis]]
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| Structural highlights
Function
INHA_MYCTU
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Triclosan has been previously shown to inhibit InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, the inhibition of which leads to the lysis of Mycobacterium tuberculosis. Using a structure-based drug design approach, a series of 5-substituted triclosan derivatives was developed. Two groups of derivatives with alkyl and aryl substituents, respectively, were identified with dramatically enhanced potency against purified InhA. The most efficacious inhibitor displayed an IC(50) value of 21 nM, which was 50-fold more potent than triclosan. X-ray crystal structures of InhA in complex with four triclosan derivatives revealed the structural basis for the inhibitory activity. Six selected triclosan derivatives were tested against isoniazid-sensitive and resistant strains of M. tuberculosis. Among those, the best inhibitor had an MIC value of 4.7 mug mL(-1) (13 muM), which represents a tenfold improvement over the bacteriocidal activity of triclosan. A subset of these triclosan analogues was more potent than isoniazid against two isoniazid-resistant M. tuberculosis strains, demonstrating the significant potential for structure-based design in the development of next generation antitubercular drugs.
Triclosan Derivatives: Towards Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis.,Freundlich JS, Wang F, Vilcheze C, Gulten G, Langley R, Schiehser GA, Jacobus DP, Jacobs WR Jr, Sacchettini JC ChemMedChem. 2009 Jan 7. PMID:19130456[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Freundlich JS, Wang F, Vilcheze C, Gulten G, Langley R, Schiehser GA, Jacobus DP, Jacobs WR Jr, Sacchettini JC. Triclosan Derivatives: Towards Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis. ChemMedChem. 2009 Jan 7. PMID:19130456 doi:10.1002/cmdc.200800261
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