View source for 4oim


==Crystal structure of Mycobacterium tuberculosis InhA in complex with inhibitor PT119 in 2.4 M acetate==
<StructureSection load='4oim' size='340' side='right'caption='[[4oim]], [[Resolution|resolution]] 1.85&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4oim]] is a 1 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=4OIM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OIM 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]] 1.848&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=JUS:2-(2-CYANOPHENOXY)-5-HEXYLPHENOL'>JUS</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=4oim FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4oim OCA], [https://pdbe.org/4oim PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4oim RCSB], [https://www.ebi.ac.uk/pdbsum/4oim PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4oim ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/INHA_MYCTU INHA_MYCTU] 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
The diaryl ethers are a novel class of antituberculosis drug candidates that inhibit InhA, the enoyl-ACP reductase involved in the fatty acid biosynthesis (FASII) pathway, and have antibacterial activity against both drug-sensitive and drug-resistant strains of Mycobacterium tuberculosis. In the present work, we demonstrate that two time-dependent B-ring modified diaryl ether InhA inhibitors have antibacterial activity in a mouse model of TB infection when delivered by intraperitoneal injection. We propose that the efficacy of these compounds is related to their residence time on the enzyme, and to identify structural features that modulate drug-target residence time in this system, we have explored the inhibition of InhA by a series of B-ring modified analogues. Seven ortho-substituted compounds were found to be time-dependent inhibitors of InhA, where the slow step leading to the final enzyme-inhibitor complex (EI*) is thought to correlate with closure and ordering of the InhA substrate binding loop. A detailed mechanistic understanding of the molecular basis for residence time in this system will facilitate the development of InhA inhibitors with improved in vivo activity.

Time-Dependent Diaryl Ether Inhibitors of InhA: Structure-Activity Relationship Studies of Enzyme Inhibition, Antibacterial Activity, and in vivo Efficacy.,Pan P, Knudson SE, Bommineni GR, Li HJ, Lai CT, Liu N, Garcia-Diaz M, Simmerling C, Patil SS, Slayden RA, Tonge PJ ChemMedChem. 2014 Apr;9(4):776-91. doi: 10.1002/cmdc.201300429. Epub 2014 Mar 11. PMID:24616444<ref>PMID:24616444</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4oim" 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: Garcia-Diaz M]]
[[Category: Lai CT]]
[[Category: Li HJ]]
[[Category: Liu N]]
[[Category: Pan P]]
[[Category: Simmerling C]]
[[Category: Tonge PJ]]