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New page: left|200px<br /><applet load="2ied" size="450" color="white" frame="true" align="right" spinBox="true" caption="2ied, resolution 2.14Å" /> '''CRYSTAL STRUCTURE of... |
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== | ==CRYSTAL STRUCTURE of ISONIAZID-RESISTANT S94A ENOYL-ACP(COA) REDUCTASE MUTANT ENZYME FROM MYCOBACTERIUM TUBERCULOSIS UNCOMPLEXED== | ||
The resumption of tuberculosis led to an increased need to understand the | <StructureSection load='2ied' size='340' side='right'caption='[[2ied]], [[Resolution|resolution]] 2.14Å' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2ied]] 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=2IED OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2IED FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.14Å</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=2ied FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2ied OCA], [https://pdbe.org/2ied PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2ied RCSB], [https://www.ebi.ac.uk/pdbsum/2ied PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2ied ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/INHA_MYCTU INHA_MYCTU] | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ie/2ied_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2ied ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The resumption of tuberculosis led to an increased need to understand the molecular mechanisms of drug action and drug resistance, which should provide significant insight into the development of newer compounds. Isoniazid (INH), the most prescribed drug to treat TB, inhibits an NADH-dependent enoyl-acyl carrier protein reductase (InhA) that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. InhA is the major target of the mode of action of isoniazid. INH is a pro-drug that needs activation to form the inhibitory INH-NAD adduct. Missense mutations in the inhA structural gene have been identified in clinical isolates of Mycobacterium tuberculosis resistant to INH. To understand the mechanism of resistance to INH, we have solved the structure of two InhA mutants (I21V and S94A), identified in INH-resistant clinical isolates, and compare them to INH-sensitive WT InhA structure in complex with the INH-NAD adduct. We also solved the structure of unliganded INH-resistant S94A protein, which is the first report on apo form of InhA. The salient features of these structures are discussed and should provide structural information to improve our understanding of the mechanism of action of, and resistance to, INH in M. tuberculosis. The unliganded structure of InhA allows identification of conformational changes upon ligand binding and should help structure-based drug design of more potent antimycobacterial agents. | |||
Crystallographic studies on the binding of isonicotinyl-NAD adduct to wild-type and isoniazid resistant 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis.,Dias MV, Vasconcelos IB, Prado AM, Fadel V, Basso LA, de Azevedo WF Jr, Santos DS J Struct Biol. 2007 Sep;159(3):369-80. Epub 2007 May 3. PMID:17588773<ref>PMID:17588773</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
[[Category: | <div class="pdbe-citations 2ied" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Enoyl-Acyl-Carrier Protein Reductase 3D structures|Enoyl-Acyl-Carrier Protein Reductase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Mycobacterium tuberculosis]] | [[Category: Mycobacterium tuberculosis]] | ||
[[Category: | [[Category: Azevedo Jr WF]] | ||
[[Category: Basso | [[Category: Basso LA]] | ||
[[Category: Dias | [[Category: Dias MVB]] | ||
[[Category: Fadel | [[Category: Fadel V]] | ||
[[Category: Prado AMX]] | |||
[[Category: Prado | [[Category: Santos DS]] | ||
[[Category: Santos | [[Category: Vasconcelos IB]] | ||
[[Category: Vasconcelos | |||
Latest revision as of 13:10, 30 August 2023
CRYSTAL STRUCTURE of ISONIAZID-RESISTANT S94A ENOYL-ACP(COA) REDUCTASE MUTANT ENZYME FROM MYCOBACTERIUM TUBERCULOSIS UNCOMPLEXEDCRYSTAL STRUCTURE of ISONIAZID-RESISTANT S94A ENOYL-ACP(COA) REDUCTASE MUTANT ENZYME FROM MYCOBACTERIUM TUBERCULOSIS UNCOMPLEXED
Structural highlights
FunctionEvolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedThe resumption of tuberculosis led to an increased need to understand the molecular mechanisms of drug action and drug resistance, which should provide significant insight into the development of newer compounds. Isoniazid (INH), the most prescribed drug to treat TB, inhibits an NADH-dependent enoyl-acyl carrier protein reductase (InhA) that provides precursors of mycolic acids, which are components of the mycobacterial cell wall. InhA is the major target of the mode of action of isoniazid. INH is a pro-drug that needs activation to form the inhibitory INH-NAD adduct. Missense mutations in the inhA structural gene have been identified in clinical isolates of Mycobacterium tuberculosis resistant to INH. To understand the mechanism of resistance to INH, we have solved the structure of two InhA mutants (I21V and S94A), identified in INH-resistant clinical isolates, and compare them to INH-sensitive WT InhA structure in complex with the INH-NAD adduct. We also solved the structure of unliganded INH-resistant S94A protein, which is the first report on apo form of InhA. The salient features of these structures are discussed and should provide structural information to improve our understanding of the mechanism of action of, and resistance to, INH in M. tuberculosis. The unliganded structure of InhA allows identification of conformational changes upon ligand binding and should help structure-based drug design of more potent antimycobacterial agents. Crystallographic studies on the binding of isonicotinyl-NAD adduct to wild-type and isoniazid resistant 2-trans-enoyl-ACP (CoA) reductase from Mycobacterium tuberculosis.,Dias MV, Vasconcelos IB, Prado AM, Fadel V, Basso LA, de Azevedo WF Jr, Santos DS J Struct Biol. 2007 Sep;159(3):369-80. Epub 2007 May 3. PMID:17588773[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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