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| ==Crystal structure of InhA_T266D:NADH complex== | | ==Crystal structure of InhA_T266D:NADH complex== |
| <StructureSection load='3of2' size='340' side='right' caption='[[3of2]], [[Resolution|resolution]] 2.00Å' scene=''> | | <StructureSection load='3of2' size='340' side='right'caption='[[3of2]], [[Resolution|resolution]] 2.00Å' scene=''> |
| == Structural highlights == | | == Structural highlights == |
| <table><tr><td colspan='2'>[[3of2]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Mycobacterium_tuberculosis Mycobacterium tuberculosis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OF2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3OF2 FirstGlance]. <br> | | <table><tr><td colspan='2'>[[3of2]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mycobacterium_tuberculosis_H37Rv Mycobacterium tuberculosis H37Rv]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OF2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3OF2 FirstGlance]. <br> |
| </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</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]] 2Å</td></tr> |
| <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3oew|3oew]], [[3oey|3oey]]</td></tr>
| | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</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, MT1531, MTCY277.05, Rv1484 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 Mycobacterium tuberculosis])</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=3of2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3of2 OCA], [https://pdbe.org/3of2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3of2 RCSB], [https://www.ebi.ac.uk/pdbsum/3of2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3of2 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=3of2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3of2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3of2 RCSB], [http://www.ebi.ac.uk/pdbsum/3of2 PDBsum]</span></td></tr> | |
| </table> | | </table> |
| <div style="background-color:#fffaf0;">
| | == Function == |
| == Publication Abstract from PubMed == | | [https://www.uniprot.org/uniprot/INHA_MYCTU INHA_MYCTU] |
| The remarkable survival ability of Mycobacterium tuberculosis in infected hosts is related to the presence of cell wall-associated mycolic acids. Despite their importance, the mechanisms that modulate expression of these lipids in response to environmental changes are unknown. Here we demonstrate that the enoyl-ACP reductase activity of InhA, an essential enzyme of the mycolic acid biosynthetic pathway and the primary target of the anti-tubercular drug isoniazid, is controlled via phosphorylation. Thr-266 is the unique kinase phosphoacceptor, both in vitro and in vivo. The physiological relevance of Thr-266 phosphorylation was demonstrated using inhA phosphoablative (T266A) or phosphomimetic (T266D/E) mutants. Enoyl reductase activity was severely impaired in the mimetic mutants in vitro, as a consequence of a reduced binding affinity to NADH. Importantly, introduction of inhA_T266D/E failed to complement growth and mycolic acid defects of an inhA-thermosensitive Mycobacterium smegmatis strain, in a similar manner to what is observed following isoniazid treatment. This study suggests that phosphorylation of InhA may represent an unusual mechanism that allows M. tuberculosis to regulate its mycolic acid content, thus offering a new approach to future anti-tuberculosis drug development.
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| Phosphorylation of InhA inhibits mycolic acid biosynthesis and growth of Mycobacterium tuberculosis.,Molle V, Gulten G, Vilcheze C, Veyron-Churlet R, Zanella-Cleon I, Sacchettini JC, Jacobs WR Jr, Kremer L Mol Microbiol. 2010 Dec;78(6):1591-605. doi:, 10.1111/j.1365-2958.2010.07446.x. Epub 2010 Nov 9. PMID:21143326<ref>PMID:21143326</ref>
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| From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| </div>
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| ==See Also== | | ==See Also== |
| *[[Enoyl-Acyl-Carrier Protein Reductase|Enoyl-Acyl-Carrier Protein Reductase]] | | *[[Enoyl-Acyl-Carrier Protein Reductase 3D structures|Enoyl-Acyl-Carrier Protein Reductase 3D structures]] |
| == References ==
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| <references/>
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| __TOC__ | | __TOC__ |
| </StructureSection> | | </StructureSection> |
| [[Category: Mycobacterium tuberculosis]] | | [[Category: Large Structures]] |
| [[Category: Gulten, G]] | | [[Category: Mycobacterium tuberculosis H37Rv]] |
| [[Category: Jr, W R.Jacobs]] | | [[Category: Gulten G]] |
| [[Category: Kremer, L]] | | [[Category: Jacobs Jr WR]] |
| [[Category: Molle, V]] | | [[Category: Kremer L]] |
| [[Category: Sacchettini, J C]] | | [[Category: Molle V]] |
| [[Category: Veyron-Churlet, R]] | | [[Category: Sacchettini JC]] |
| [[Category: Vilcheze, C]] | | [[Category: Veyron-Churlet R]] |
| [[Category: Zanella-Cleon, I]] | | [[Category: Vilcheze C]] |
| [[Category: Enoyl-reductase]]
| | [[Category: Zanella-Cleon I]] |
| [[Category: Oxidoreductase]]
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