5m4p - Revision history

OCA at 18:25, 1 November 2023

OCA — Wed, 01 Nov 2023 18:25:56 GMT

←Older revision		Revision as of 18:25, 1 November 2023
Line 1:		Line 1:

	==Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase==		==Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase==
-	<StructureSection load='5m4p' size='340' side='right' caption='[[5m4p]], [[Resolution\|resolution]] 2.30Å' scene=''>	+	<StructureSection load='5m4p' size='340' side='right'caption='[[5m4p]], [[Resolution\|resolution]] 2.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5m4p]] is a 1 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M4P OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5M4P FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5m4p]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M4P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5M4P FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7FE:~{N}-[4-(2-CHLORANYL-5-METHYL-PYRIMIDIN-4-YL)PHENYL]-2,4-BIS(OXIDANYL)-~{N}-[[4-(PYRROLIDIN-1-YLMETHYL)PHENYL]METHYL]BENZAMIDE'>7FE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=TF3:N-(2-AMINOETHYL)-2-{3-CHLORO-4-[(4-ISOPROPYLBENZYL)OXY]PHENYL}+ACETAMIDE'>TF3</scene~~></td></tr>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 2.3Å</td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDK2, PDHK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7FE:~{N}-[4-(2-CHLORANYL-5-METHYL-PYRIMIDIN-4-YL)PHENYL]-2,4-BIS(OXIDANYL)-~{N}-[[4-(PYRROLIDIN-1-YLMETHYL)PHENYL]METHYL]BENZAMIDE'>7FE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=TF3:N-(2-AMINOETHYL)-2-{3-CHLORO-4-[(4-ISOPROPYLBENZYL)OXY]PHENYL}+ACETAMIDE'>TF3</scene></td></tr>
-	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Pyruvate_dehydrogenase_(acetyl-transferring)]_kinase [Pyruvate dehydrogenase (acetyl-transferring)] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.2 2.7.11.2] </span></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=5m4p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m4p OCA], [https://pdbe.org/5m4p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5m4p RCSB], [https://www.ebi.ac.uk/pdbsum/5m4p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5m4p ProSAT]</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=5m4p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m4p OCA], [~~http~~://pdbe.org/5m4p PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5m4p RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5m4p PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5m4p ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/PDK2_HUMAN PDK2_HUMAN]] Serine/threonine kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis.<ref>PMID:7499431</ref> <ref>PMID:9787110</ref> <ref>PMID:17222789</ref> <ref>PMID:19833728</ref> <ref>PMID:21283817</ref> <ref>PMID:22123926</ref>	+	[https://www.uniprot.org/uniprot/PDK2_HUMAN PDK2_HUMAN] Serine/threonine kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis.<ref>PMID:7499431</ref> <ref>PMID:9787110</ref> <ref>PMID:17222789</ref> <ref>PMID:19833728</ref> <ref>PMID:21283817</ref> <ref>PMID:22123926</ref>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 27:		Line 26:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Baker, L M~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Brough, P~~]]	+	[[Category: Baker LM]]
-	[[Category: ~~Surgenor, A~~]]	+	[[Category: Brough P]]
-	[[Category: ~~Cancer]]~~	+	[[Category: Surgenor A]]
-	~~[[Category: Fragment screening]]~~	+
-	~~[[Category: Hsp90]]~~	+
-	~~[[Category: Kinase inhibitor]]~~	+
-	~~[[Category: Off-rate screening]]~~	+
-	~~[[Category: Pdhk]]~~	+
-	~~[[Category: Pdk1]]~~	+
-	~~[[Category: Pdk2]]~~	+
-	~~[[Category: Pdk3]]~~	+
-	~~[[Category: Pdk4]]~~	+
-	~~[[Category: Spr]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 06:27, 24 October 2018

OCA — Wed, 24 Oct 2018 06:27:38 GMT

←Older revision		Revision as of 06:27, 24 October 2018
Line 3:		Line 3:
	<StructureSection load='5m4p' size='340' side='right' caption='[[5m4p]], [[Resolution\|resolution]] 2.30Å' scene=''>		<StructureSection load='5m4p' size='340' side='right' caption='[[5m4p]], [[Resolution\|resolution]] 2.30Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5m4p]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M4P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M4P FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5m4p]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M4P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M4P FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7FE:~{N}-[4-(2-CHLORANYL-5-METHYL-PYRIMIDIN-4-YL)PHENYL]-2,4-BIS(OXIDANYL)-~{N}-[[4-(PYRROLIDIN-1-YLMETHYL)PHENYL]METHYL]BENZAMIDE'>7FE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=TF3:N-(2-AMINOETHYL)-2-{3-CHLORO-4-[(4-ISOPROPYLBENZYL)OXY]PHENYL}+ACETAMIDE'>TF3</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7FE:~{N}-[4-(2-CHLORANYL-5-METHYL-PYRIMIDIN-4-YL)PHENYL]-2,4-BIS(OXIDANYL)-~{N}-[[4-(PYRROLIDIN-1-YLMETHYL)PHENYL]METHYL]BENZAMIDE'>7FE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=TF3:N-(2-AMINOETHYL)-2-{3-CHLORO-4-[(4-ISOPROPYLBENZYL)OXY]PHENYL}+ACETAMIDE'>TF3</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDK2, PDHK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Pyruvate_dehydrogenase_(acetyl-transferring)]_kinase [Pyruvate dehydrogenase (acetyl-transferring)] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.2 2.7.11.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Pyruvate_dehydrogenase_(acetyl-transferring)]_kinase [Pyruvate dehydrogenase (acetyl-transferring)] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.2 2.7.11.2] </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=5m4p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m4p OCA], [http://pdbe.org/5m4p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m4p RCSB], [http://www.ebi.ac.uk/pdbsum/5m4p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m4p ProSAT]</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=5m4p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m4p OCA], [http://pdbe.org/5m4p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m4p RCSB], [http://www.ebi.ac.uk/pdbsum/5m4p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m4p ProSAT]</span></td></tr>
Line 19:		Line 20:
	</div>		</div>
	<div class="pdbe-citations 5m4p" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 5m4p" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Pyruvate dehydrogenase kinase\|Pyruvate dehydrogenase kinase]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Baker, L M]]		[[Category: Baker, L M]]
	[[Category: Brough, P]]		[[Category: Brough, P]]

OCA at 01:38, 11 March 2017

OCA — Sat, 11 Mar 2017 01:38:18 GMT

←Older revision		Revision as of 01:38, 11 March 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5m4p is ~~ON HOLD~~	+	==Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase==
		+	<StructureSection load='5m4p' size='340' side='right' caption='[[5m4p]], [[Resolution\|resolution]] 2.30Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5m4p]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M4P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M4P FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7FE:~{N}-[4-(2-CHLORANYL-5-METHYL-PYRIMIDIN-4-YL)PHENYL]-2,4-BIS(OXIDANYL)-~{N}-[[4-(PYRROLIDIN-1-YLMETHYL)PHENYL]METHYL]BENZAMIDE'>7FE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=TF3:N-(2-AMINOETHYL)-2-{3-CHLORO-4-[(4-ISOPROPYLBENZYL)OXY]PHENYL}+ACETAMIDE'>TF3</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/[Pyruvate_dehydrogenase_(acetyl-transferring)]_kinase [Pyruvate dehydrogenase (acetyl-transferring)] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.2 2.7.11.2] </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=5m4p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m4p OCA], [http://pdbe.org/5m4p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m4p RCSB], [http://www.ebi.ac.uk/pdbsum/5m4p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m4p ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PDK2_HUMAN PDK2_HUMAN]] Serine/threonine kinase that plays a key role in the regulation of glucose and fatty acid metabolism and homeostasis via phosphorylation of the pyruvate dehydrogenase subunits PDHA1 and PDHA2. This inhibits pyruvate dehydrogenase activity, and thereby regulates metabolite flux through the tricarboxylic acid cycle, down-regulates aerobic respiration and inhibits the formation of acetyl-coenzyme A from pyruvate. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism. Mediates cellular responses to insulin. Plays an important role in maintaining normal blood glucose levels and in metabolic adaptation to nutrient availability. Via its regulation of pyruvate dehydrogenase activity, plays an important role in maintaining normal blood pH and in preventing the accumulation of ketone bodies under starvation. Plays a role in the regulation of cell proliferation and in resistance to apoptosis under oxidative stress. Plays a role in p53/TP53-mediated apoptosis.<ref>PMID:7499431</ref> <ref>PMID:9787110</ref> <ref>PMID:17222789</ref> <ref>PMID:19833728</ref> <ref>PMID:21283817</ref> <ref>PMID:22123926</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1alpha subunit in the PC3 cancer cell line in vitro.

-	~~Authors:~~ Baker, L~~.M.~~, ~~Brough~~, P., Surgenor, A.	+	Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase.,Brough PA, Baker L, Bedford S, Brown K, Chavda S, Chell V, D'Alessandro J, Davies NG, Davis B, Le Strat L, Macias AT, Maddox D, Mahon PC, Massey AJ, Matassova N, McKenna S, Moore JD, Murray JB, Northfield CJ, Parry C, Parsons R, Roughley SD, Shaw T, Simmonite H, Stokes S, Surgenor A, Stefaniak E, Robertson A, Wang Y, Webb P, Whitehead N, Wood M J Med Chem. 2017 Feb 15. doi: 10.1021/acs.jmedchem.6b01478. PMID:28199108<ref>PMID:28199108</ref>

-	~~Description: Application~~ of ~~Off-Rate Screening in~~ the ~~Identification~~ of ~~Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category: Unreleased Structures]]~~	+	</div>
-	~~[[Category~~: ~~Surgenor, A]]~~	+	<div class="pdbe-citations 5m4p" style="background-color:#fffaf0;"></div>
-	[[Category: Baker, L.M]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Baker, L M]]
	[[Category: Brough, P]]		[[Category: Brough, P]]
		+	[[Category: Surgenor, A]]
		+	[[Category: Cancer]]
		+	[[Category: Fragment screening]]
		+	[[Category: Hsp90]]
		+	[[Category: Kinase inhibitor]]
		+	[[Category: Off-rate screening]]
		+	[[Category: Pdhk]]
		+	[[Category: Pdk1]]
		+	[[Category: Pdk2]]
		+	[[Category: Pdk3]]
		+	[[Category: Pdk4]]
		+	[[Category: Spr]]
		+	[[Category: Transferase]]

OCA: Protected "5m4p" [edit=sysop:move=sysop]

OCA — Wed, 26 Oct 2016 16:24:29 GMT

Protected "5m4p" [edit=sysop:move=sysop]

←Older revision

Revision as of 16:24, 26 October 2016

OCA: New page: '''Unreleased structure''' The entry 5m4p is ON HOLD Authors: Baker, L.M., Brough, P., Surgenor, A. Description: Application of Off-Rate Screening in the Identification of Novel Pan-Is...

OCA — Wed, 26 Oct 2016 16:24:28 GMT

New page: '''Unreleased structure''' The entry 5m4p is ON HOLD Authors: Baker, L.M., Brough, P., Surgenor, A. Description: Application of Off-Rate Screening in the Identification of Novel Pan-Is...

New page

'''Unreleased structure'''

The entry 5m4p is ON HOLD

Authors: Baker, L.M., Brough, P., Surgenor, A.

Description: Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase
[[Category: Unreleased Structures]]
[[Category: Surgenor, A]]
[[Category: Baker, L.M]]
[[Category: Brough, P]]