4oyr: Difference between revisions

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-'''Unreleased structure'''
-The entry 4oyr is ON HOLD  until Paper Publication
+==Competition of the small inhibitor PT91 with large fatty acyl substrate of the Mycobacterium tuberculosis enoyl-ACP reductase InhA by induced substrate-binding loop refolding==
+<StructureSection load='4oyr' size='340' side='right'caption='[[4oyr]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[4oyr]] 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=4OYR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OYR 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]] 2.2995&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1US:2-(2-CHLORANYLPHENOXY)-5-HEXYL-PHENOL'>1US</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=4oyr FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4oyr OCA], [https://pdbe.org/4oyr PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4oyr RCSB], [https://www.ebi.ac.uk/pdbsum/4oyr PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4oyr ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/INHA_MYCTU INHA_MYCTU]
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Slow-onset enzyme inhibitors are of great interest for drug discovery programs since the slow dissociation of the inhibitor from the drug-target complex results in sustained target occupancy leading to improved pharmacodynamics. However, the structural basis for slow-onset inhibition is often not fully understood, hindering the development of structure-kinetic relationships and the rational optimization of drug-target residence time. Previously we demonstrated that slow-onset inhibition of the Mycobacterium tuberculosis enoyl-ACP reductase InhA correlated with motions of a substrate-binding loop (SBL) near the active site. In the present work, X-ray crystallography and molecular dynamics simulations have been used to map the structural and energetic changes of the SBL that occur upon enzyme inhibition. Helix-6 within the SBL adopts an open conformation when the inhibitor structure or binding kinetics is substrate-like. In contrast, slow-onset inhibition results in large-scale local refolding in which helix-6 adopts a closed conformation not normally populated during substrate turnover. The open and closed conformations of helix-6 are hypothesized to represent the EI and EI* states on the two-step induced-fit reaction coordinate for enzyme inhibition. These two states were used as the end points for nudged elastic band molecular dynamics simulations resulting in two-dimensional potential energy profiles that reveal the barrier between EI and EI*, thus rationalizing the binding kinetics observed with different inhibitors. Our findings indicate that the structural basis for slow-onset kinetics can be understood once the structures of both EI and EI* have been identified, thus providing a starting point for the rational control of enzyme-inhibitor binding kinetics.
-Authors: Li, H.J., Pan, P., Lai, C.T., Liu, N., Garcia-Diaz, M., Simmerling, C., Tonge, P.J.
+A Structural and Energetic Model for the Slow-Onset Inhibition of the Mycobacterium tuberculosis Enoyl-ACP Reductase InhA.,Li HJ, Lai CT, Pan P, Yu W, Liu N, Bommineni GR, Garcia-Diaz M, Simmerling C, Tonge PJ ACS Chem Biol. 2014 Apr 18;9(4):986-93. doi: 10.1021/cb400896g. Epub 2014 Mar 10. PMID:24527857<ref>PMID:24527857</ref>
-Description: Competition of the small inhibitor PT91 with large fatty acyl substrate of the Mycobacterium tuberculosis enoyl-ACP reductase InhA by induced substrate-binding loop refolding
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 4oyr" 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]]