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5cp8

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==The effect of isoleucine to alanine mutation on InhA enzyme crystallization pattern and substrate binding loop conformation and flexibility==
==The effect of isoleucine to alanine mutation on InhA enzyme crystallization pattern and substrate binding loop conformation and flexibility==
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<StructureSection load='5cp8' size='340' side='right' caption='[[5cp8]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
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<StructureSection load='5cp8' size='340' side='right'caption='[[5cp8]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5cp8]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5CP8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5CP8 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5cp8]] 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=5CP8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5CP8 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=ETE:2-{2-[2-2-(METHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>ETE</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=TCU:5-HEXYL-2-(2-METHYLPHENOXY)PHENOL'>TCU</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.4&#8491;</td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5coq|5coq]], [[5cpf|5cpf]]</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EPE:4-(2-HYDROXYETHYL)-1-PIPERAZINE+ETHANESULFONIC+ACID'>EPE</scene>, <scene name='pdbligand=ETE:2-{2-[2-2-(METHOXY-ETHOXY)-ETHOXY]-ETHOXY}-ETHANOL'>ETE</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=TCU:5-HEXYL-2-(2-METHYLPHENOXY)PHENOL'>TCU</scene></td></tr>
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<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'>[https://proteopedia.org/fgij/fg.htm?mol=5cp8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cp8 OCA], [https://pdbe.org/5cp8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5cp8 RCSB], [https://www.ebi.ac.uk/pdbsum/5cp8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5cp8 ProSAT]</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=5cp8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5cp8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=5cp8 RCSB], [http://www.ebi.ac.uk/pdbsum/5cp8 PDBsum]</span></td></tr>
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</table>
</table>
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<div style="background-color:#fffaf0;">
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== Function ==
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== Publication Abstract from PubMed ==
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[https://www.uniprot.org/uniprot/INHA_MYCTU INHA_MYCTU]
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Slow-onset enzyme inhibitors are the subject of considerable interest as an approach to increasing the potency of pharmaceutical compounds by extending the residence time of the inhibitor on the target (the lifetime of the drug-receptor complex). However, rational modulation of residence time presents significant challenges because it requires additional mechanistic insight, such as the nature of the transition state for postbinding isomerization. Our previous work, based on X-ray crystallography, enzyme kinetics, and molecular dynamics simulation, suggested that the slow step in inhibition of the Mycobacterium tuberculosis enoyl-ACP reductase InhA involves a change in the conformation of the substrate binding loop from an open state in the initial enzyme-inhibitor complex to a closed state in the final enzyme-inhibitor complex. Here, we use multidimensional free energy landscapes for loop isomerization to obtain a computational model for the transition state. The results suggest that slow-onset inhibitors crowd key side chains on helices that slide past each other during isomerization, resulting in a steric clash. The landscapes become significantly flatter when residues involved in the steric clash are replaced with alanine. Importantly, this lower barrier can be increased by rational inhibitor redesign to restore the steric clash. Crystallographic studies and enzyme kinetics confirm the predicted effects on loop structure and flexibility, as well as inhibitor residence time. These loss and regain of function studies validate our mechanistic hypothesis for interactions controlling substrate binding loop isomerization, providing a platform for the future design of inhibitors with longer residence times and better in vivo potency. Similar opportunities for slow-onset inhibition via the same mechanism are identified in other pathogens.
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Rational Modulation of the Induced-Fit Conformational Change for Slow-Onset Inhibition in Mycobacterium tuberculosis InhA.,Lai CT, Li HJ, Yu W, Shah S, Bommineni GR, Perrone V, Garcia-Diaz M, Tonge PJ, Simmerling C Biochemistry. 2015 Aug 4;54(30):4683-91. doi: 10.1021/acs.biochem.5b00284. Epub, 2015 Jul 24. PMID:26147157<ref>PMID:26147157</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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==See Also==
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</div>
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*[[Enoyl-Acyl-Carrier Protein Reductase 3D structures|Enoyl-Acyl-Carrier Protein Reductase 3D structures]]
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== References ==
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<references/>
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Garcia-Diaz, M]]
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[[Category: Large Structures]]
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[[Category: Li, H J]]
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[[Category: Mycobacterium tuberculosis]]
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[[Category: Simmerling, C]]
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[[Category: Bommineni GR]]
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[[Category: Tonge, P J]]
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[[Category: Garcia-Diaz M]]
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[[Category: Crystal packing fatty acid biosynthesis slow-onset inhibition free energy calculation]]
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[[Category: Lai C-T]]
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[[Category: Oxidoreductase]]
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[[Category: Li H-J]]
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[[Category: Liu N]]
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[[Category: Perrone V]]
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[[Category: Shah S]]
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[[Category: Simmerling C]]
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[[Category: Tonge PJ]]
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[[Category: Yu W]]

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The effect of isoleucine to alanine mutation on InhA enzyme crystallization pattern and substrate binding loop conformation and flexibility

PDB ID 5cp8

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