5ugs - Revision history

OCA at 12:36, 23 September 2020

2020-09-23T12:36:20Z

←Older revision		Revision as of 12:36, 23 September 2020
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	==Crystal structure of M. tuberculosis InhA inhibited by PT501==		==Crystal structure of M. tuberculosis InhA inhibited by PT501==
-	<StructureSection load='5ugs' size='340' side='right' caption='[[5ugs]], [[Resolution\|resolution]] 2.80Å' scene=''>	+	<StructureSection load='5ugs' size='340' side='right'caption='[[5ugs]], [[Resolution\|resolution]] 2.80Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5ugs]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UGS OCA]. For a <b>guided tour on the structure components</b> use [http://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5UGS FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5ugs]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_tuberculosis"_(zopf_1883)_klein_1884 "bacillus tuberculosis" (zopf 1883) klein 1884]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UGS OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5UGS FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=XT5:5-[(4-CYCLOPROPYL-1,2,3-TRIAZOL-1-YL)METHYL]-2-(2-METHYLPHENOXY)PHENOL'>XT5</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=XT5:5-[(4-CYCLOPROPYL-1,2,3-TRIAZOL-1-YL)METHYL]-2-(2-METHYLPHENOXY)PHENOL'>XT5</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">inhA, Rv1484, MTCY277.05 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=1773 "Bacillus tuberculosis" (Zopf 1883) Klein 1884])</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>		<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>
-	<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=5ugs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ugs OCA], [http://pdbe.org/5ugs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ugs RCSB], [http://www.ebi.ac.uk/pdbsum/5ugs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ugs ProSAT]</span></td></tr>	+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5ugs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ugs OCA], [http://pdbe.org/5ugs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ugs RCSB], [http://www.ebi.ac.uk/pdbsum/5ugs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ugs ProSAT]</span></td></tr>
	</table>		</table>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
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	</div>		</div>
	<div class="pdbe-citations 5ugs" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5ugs" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Enoyl-Acyl-Carrier Protein Reductase 3D structures\|Enoyl-Acyl-Carrier Protein Reductase 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Large Structures]]
	[[Category: Eltschkner, S]]		[[Category: Eltschkner, S]]
	[[Category: Kisker, C]]		[[Category: Kisker, C]]

OCA at 17:47, 10 March 2017

2017-03-10T17:47:00Z

←Older revision		Revision as of 17:47, 10 March 2017
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-	'''Unreleased structure'''

-	~~The entry~~ 5ugs is ~~ON HOLD until Paper~~ Publication	+	==Crystal structure of M. tuberculosis InhA inhibited by PT501==
		+	<StructureSection load='5ugs' size='340' side='right' caption='[[5ugs]], [[Resolution\|resolution]] 2.80Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5ugs]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UGS OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UGS FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAD:NICOTINAMIDE-ADENINE-DINUCLEOTIDE'>NAD</scene>, <scene name='pdbligand=XT5:5-[(4-CYCLOPROPYL-1,2,3-TRIAZOL-1-YL)METHYL]-2-(2-METHYLPHENOXY)PHENOL'>XT5</scene></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>
		+	<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=5ugs FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ugs OCA], [http://pdbe.org/5ugs PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ugs RCSB], [http://www.ebi.ac.uk/pdbsum/5ugs PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ugs ProSAT]</span></td></tr>
		+	</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	A critical goal of lead compound selection and optimization is to maximize target engagement while minimizing off-target binding. Since target engagement is a function of both the thermodynamics and kinetics of drug-target interactions, it follows that the structures of both the ground states and transition states on the binding reaction coordinate are needed to rationally modulate the lifetime of the drug-target complex. Previously, we predicted the structure of the rate-limiting transition state that controlled the time-dependent inhibition of the enoyl-ACP reductase InhA. This led to the discovery of a triazole-containing diphenyl ether with an increased residence time on InhA due to transition-state destabilization rather than ground-state stabilization. In the present work, we evaluate the inhibition of InhA by 14 triazole-based diphenyl ethers and use a combination of enzyme kinetics and X-ray crystallography to generate a structure-kinetic relationship for time-dependent binding. We show that the triazole motif slows the rate of formation for the final drug-target complex by up to 3 orders of magnitude. In addition, we identify a novel inhibitor with a residence time on InhA of 220 min, which is 3.5-fold longer than that of the INH-NAD adduct formed by the tuberculosis drug, isoniazid. This study provides a clear example in which the lifetime of the drug-target complex is controlled by interactions in the transition state for inhibitor binding rather than the ground state of the enzyme-inhibitor complex, and demonstrates the important role that on-rates can play in drug-target residence time.

-	~~Authors~~:	+	Evaluating the Contribution of Transition-State Destabilization to Changes in the Residence Time of Triazole-Based InhA Inhibitors.,Spagnuolo LA, Eltschkner S, Yu W, Daryaee F, Davoodi S, Knudson SE, Allen EK, Merino J, Pschibul A, Moree B, Thivalapill N, Truglio JJ, Salafsky J, Slayden RA, Kisker C, Tonge PJ J Am Chem Soc. 2017 Mar 8;139(9):3417-3429. doi: 10.1021/jacs.6b11148. Epub 2017 , Feb 22. PMID:28151657<ref>PMID:28151657</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5ugs" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Eltschkner, S]]
		+	[[Category: Kisker, C]]
		+	[[Category: Pschibul, A]]
		+	[[Category: Spagnuolo, L A]]
		+	[[Category: Tonge, P J]]
		+	[[Category: Yu, W]]
		+	[[Category: Bacterial enoyl-acp reductase]]
		+	[[Category: Diphenylether]]
		+	[[Category: Oxidoreductase]]
		+	[[Category: Residence time]]

OCA at 21:57, 25 January 2017

2017-01-25T21:57:22Z

←Older revision		Revision as of 21:57, 25 January 2017
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 5ugs is ON HOLD	+	The entry 5ugs is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "5ugs" [edit=sysop:move=sysop]

2017-01-18T14:58:46Z

Protected "5ugs" [edit=sysop:move=sysop]

←Older revision

Revision as of 14:58, 18 January 2017

OCA: New page: '''Unreleased structure''' The entry 5ugs is ON HOLD Authors: Description: Category: Unreleased Structures

2017-01-18T14:58:45Z

New page: '''Unreleased structure''' The entry 5ugs is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 5ugs is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]