4mp2 - Revision history

OCA at 12:28, 1 March 2024

OCA — Fri, 01 Mar 2024 12:28:04 GMT

←Older revision		Revision as of 12:28, 1 March 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4mp2]] 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=4MP2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MP2 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4mp2]] 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=4MP2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MP2 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PV1:(5-BROMO-2,4-DIHYDROXYPHENYL)(1,3-DIHYDRO-2H-ISOINDOL-2-YL)METHANONE'>PV1</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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]] 1.751Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PV1:(5-BROMO-2,4-DIHYDROXYPHENYL)(1,3-DIHYDRO-2H-ISOINDOL-2-YL)METHANONE'>PV1</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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=4mp2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mp2 OCA], [https://pdbe.org/4mp2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mp2 RCSB], [https://www.ebi.ac.uk/pdbsum/4mp2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mp2 ProSAT]</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=4mp2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mp2 OCA], [https://pdbe.org/4mp2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mp2 RCSB], [https://www.ebi.ac.uk/pdbsum/4mp2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mp2 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
	[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>		[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;">
-	== Publication Abstract from PubMed ==
-	Pyruvate dehydrogenase kinase isoforms (PDKs 1 - 4) negatively regulate activity of the mitochondrial pyruvate dehydrogenase complex (PDC) by reversible phosphorylation. PDK isoforms are up-regulated in obesity, diabetes, heart failure and cancer and are potential therapeutic targets for these important human diseases. Here, we employed structure-guided design to convert a known Hsp90 inhibitor to a series of highly specific PDK inhibitors, based on structural conservation in the ATP-binding pocket. The key step involved the substitution of a carbonyl group in the parent compound with a sulfonyl in the PDK inhibitors. The final compound of this series, 2-[(2,4-dihydroxyphenyl)sulfonyl] isoindoline-4,6-diol, designated PS10, inhibits all four PDK isoforms with IC50 = 0.8 muM for PDK2. The administration of PS10 (70 mg/kg) to diet-induced obese mice significantly augments PDC activity with reduced phosphorylation in different tissues. Prolonged PS10 treatments result in improved glucose tolerance and notably lessened hepatic steatosis in the mouse model. The results support the pharmacological approach of targeting PDK to control both glucose and fat levels in obesity and type 2 diabetes.
-
-	Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket.,Tso SC, Qi X, Gui WJ, Wu CY, Chuang JL, Wernstedt-Asterholm I, Morlock LK, Owens KR, Scherer PE, Williams NS, Tambar UK, Wynn RM, Chuang DT J Biol Chem. 2013 Dec 19. PMID:24356970<ref>PMID:24356970</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 4mp2" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 09:59, 28 December 2022

OCA — Wed, 28 Dec 2022 09:59:05 GMT

←Older revision		Revision as of 09:59, 28 December 2022
Line 1:		Line 1:

	==Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1==		==Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1==
-	<StructureSection load='4mp2' size='340' side='right' caption='[[4mp2]], [[Resolution\|resolution]] 1.75Å' scene=''>	+	<StructureSection load='4mp2' size='340' side='right'caption='[[4mp2]], [[Resolution\|resolution]] 1.75Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[4mp2]] 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=4MP2 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=4MP2 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[4mp2]] 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=4MP2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MP2 FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PV1:(5-BROMO-2,4-DIHYDROXYPHENYL)(1,3-DIHYDRO-2H-ISOINDOL-2-YL)METHANONE'>PV1</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene~~></td></tr>~~	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PV1:(5-BROMO-2,4-DIHYDROXYPHENYL)(1,3-DIHYDRO-2H-ISOINDOL-2-YL)METHANONE'>PV1</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene></td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4mp7\|4mp7]], [[4mpc\|4mpc]], [[4mpe\|4mpe]]</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=4mp2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mp2 OCA], [https://pdbe.org/4mp2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mp2 RCSB], [https://www.ebi.ac.uk/pdbsum/4mp2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mp2 ProSAT]</span></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='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=4mp2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mp2 OCA], [~~http~~://pdbe.org/4mp2 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=4mp2 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/4mp2 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=4mp2 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 28:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: Chuang~~, D T~~]]	+	[[Category: Large Structures]]
-	[[Category: Chuang~~, J L~~]]	+	[[Category: Chuang DT]]
-	[[Category: Gui~~, W J~~]]	+	[[Category: Chuang JL]]
-	[[Category: Qi, X]]	+	[[Category: Gui WJ]]
-	[[Category: Tambar~~, U K~~]]	+	[[Category: Qi X]]
-	[[Category: Tso~~, S C~~]]	+	[[Category: Tambar UK]]
-	[[Category: Wu~~, C Y~~]]	+	[[Category: Tso SC]]
-	[[Category: Wynn~~, R M]]~~	+	[[Category: Wu CY]]
-	~~[[Category: Bergerat nucleotide-binding fold]]~~	+	[[Category: Wynn RM]]
-	~~[[Category: Cancer]]~~	+
-	~~[[Category: Ghkl protein kinase]]~~	+
-	~~[[Category: Hepatic steatosis]]~~	+
-	~~[[Category: Impaired glucose oxidation]]~~	+
-	~~[[Category: Mitochondrial protein kinase]]~~	+
-	~~[[Category: Protein kinase]]~~	+
-	~~[[Category: Pyruvate dehydrogenase complex]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex]]~~	+
-	~~[[Category: Type 2 diabetes~~]]	+

OCA at 18:37, 5 August 2016

OCA — Fri, 05 Aug 2016 18:37:55 GMT

←Older revision		Revision as of 18:37, 5 August 2016
Line 1:		Line 1:
		+
	==Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1==		==Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1==
	<StructureSection load='4mp2' size='340' side='right' caption='[[4mp2]], [[Resolution\|resolution]] 1.75Å' scene=''>		<StructureSection load='4mp2' size='340' side='right' caption='[[4mp2]], [[Resolution\|resolution]] 1.75Å' scene=''>
Line 7:		Line 8:
	<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='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=4mp2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mp2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mp2 RCSB], [http://www.ebi.ac.uk/pdbsum/4mp2 PDBsum]</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=4mp2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mp2 OCA], [http://pdbe.org/4mp2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mp2 RCSB], [http://www.ebi.ac.uk/pdbsum/4mp2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mp2 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 19:		Line 20:
	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>		From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+	<div class="pdbe-citations 4mp2" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==

OCA at 04:52, 25 December 2014

OCA — Thu, 25 Dec 2014 04:52:53 GMT

←Older revision		Revision as of 04:52, 25 December 2014
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[4mp2]] 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=4MP2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MP2 FirstGlance]. <br>		<table><tr><td colspan='2'>[[4mp2]] 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=4MP2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MP2 FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PV1:(5-BROMO-2,4-DIHYDROXYPHENYL)(1,3-DIHYDRO-2H-ISOINDOL-2-YL)METHANONE'>PV1</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PV1:(5-BROMO-2,4-DIHYDROXYPHENYL)(1,3-DIHYDRO-2H-ISOINDOL-2-YL)METHANONE'>PV1</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4mp7\|4mp7]], [[4mpc\|4mpc]], [[4mpe\|4mpe]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4mp7\|4mp7]], [[4mpc\|4mpc]], [[4mpe\|4mpe]]</td></tr>
-	<tr><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='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><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mp2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mp2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mp2 RCSB], [http://www.ebi.ac.uk/pdbsum/4mp2 PDBsum]</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=4mp2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mp2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mp2 RCSB], [http://www.ebi.ac.uk/pdbsum/4mp2 PDBsum]</span></td></tr>
-	<table>	+	</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;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
Line 15:		Line 17:
	Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket.,Tso SC, Qi X, Gui WJ, Wu CY, Chuang JL, Wernstedt-Asterholm I, Morlock LK, Owens KR, Scherer PE, Williams NS, Tambar UK, Wynn RM, Chuang DT J Biol Chem. 2013 Dec 19. PMID:24356970<ref>PMID:24356970</ref>		Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket.,Tso SC, Qi X, Gui WJ, Wu CY, Chuang JL, Wernstedt-Asterholm I, Morlock LK, Owens KR, Scherer PE, Williams NS, Tambar UK, Wynn RM, Chuang DT J Biol Chem. 2013 Dec 19. PMID:24356970<ref>PMID:24356970</ref>

-	From ~~MEDLINEÂ®~~/~~PubMedÂ®~~, a database of the U.S. National Library of Medicine.<br>	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
	</div>		</div>
		+
		+	==See Also==
		+	*[[Pyruvate dehydrogenase kinase\|Pyruvate dehydrogenase kinase]]
	== References ==		== References ==
	<references/>		<references/>
Line 22:		Line 27:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
-	[[Category: Chuang, D T.]]	+	[[Category: Chuang, D T]]
-	[[Category: Chuang, J L.]]	+	[[Category: Chuang, J L]]
-	[[Category: Gui, W J.]]	+	[[Category: Gui, W J]]
-	[[Category: Qi, X.]]	+	[[Category: Qi, X]]
-	[[Category: Tambar, U K.]]	+	[[Category: Tambar, U K]]
-	[[Category: Tso, S C.]]	+	[[Category: Tso, S C]]
-	[[Category: Wu, C Y.]]	+	[[Category: Wu, C Y]]
-	[[Category: Wynn, R M.]]	+	[[Category: Wynn, R M]]
	[[Category: Bergerat nucleotide-binding fold]]		[[Category: Bergerat nucleotide-binding fold]]
	[[Category: Cancer]]		[[Category: Cancer]]

OCA at 13:35, 18 May 2014

OCA — Sun, 18 May 2014 13:35:53 GMT

←Older revision		Revision as of 13:35, 18 May 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_4mp2\| PDB=4mp2 \| SCENE= }}~~	+	==Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1==
-	===Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1===	+	<StructureSection load='4mp2' size='340' side='right' caption='[[4mp2]], [[Resolution\|resolution]] 1.75Å' scene=''>
-	~~{{ABSTRACT_PUBMED_24356970}}~~	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[4mp2]] 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=4MP2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MP2 FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PV1:(5-BROMO-2,4-DIHYDROXYPHENYL)(1,3-DIHYDRO-2H-ISOINDOL-2-YL)METHANONE'>PV1</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene><br>
		+	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[4mp7\|4mp7]], [[4mpc\|4mpc]], [[4mpe\|4mpe]]</td></tr>
		+	<tr><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><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><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4mp2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mp2 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4mp2 RCSB], [http://www.ebi.ac.uk/pdbsum/4mp2 PDBsum]</span></td></tr>
		+	<table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Pyruvate dehydrogenase kinase isoforms (PDKs 1 - 4) negatively regulate activity of the mitochondrial pyruvate dehydrogenase complex (PDC) by reversible phosphorylation. PDK isoforms are up-regulated in obesity, diabetes, heart failure and cancer and are potential therapeutic targets for these important human diseases. Here, we employed structure-guided design to convert a known Hsp90 inhibitor to a series of highly specific PDK inhibitors, based on structural conservation in the ATP-binding pocket. The key step involved the substitution of a carbonyl group in the parent compound with a sulfonyl in the PDK inhibitors. The final compound of this series, 2-[(2,4-dihydroxyphenyl)sulfonyl] isoindoline-4,6-diol, designated PS10, inhibits all four PDK isoforms with IC50 = 0.8 muM for PDK2. The administration of PS10 (70 mg/kg) to diet-induced obese mice significantly augments PDC activity with reduced phosphorylation in different tissues. Prolonged PS10 treatments result in improved glucose tolerance and notably lessened hepatic steatosis in the mouse model. The results support the pharmacological approach of targeting PDK to control both glucose and fat levels in obesity and type 2 diabetes.

-	~~==Function==~~	+	Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket.,Tso SC, Qi X, Gui WJ, Wu CY, Chuang JL, Wernstedt-Asterholm I, Morlock LK, Owens KR, Scherer PE, Williams NS, Tambar UK, Wynn RM, Chuang DT J Biol Chem. 2013 Dec 19. PMID:24356970<ref>PMID:24356970</ref>
-	~~[[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>	+

-	~~==About this Structure==~~	+	From MEDLINEÂ®/PubMedÂ®, a database of the U.S. National Library of Medicine.<br>
-	~~[[4mp2]] is~~ a ~~1 chain structure~~. ~~Full crystallographic information is available from [http://oca~~.~~weizmann~~.~~ac.il~~/~~oca-bin/ocashort?id=4MP2 OCA].~~	+	</div>
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	~~<ref group="xtra">PMID:024356970</ref>~~<references ~~group="xtra"~~/><~~references~~/>	+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
	[[Category: Chuang, D T.]]		[[Category: Chuang, D T.]]
	[[Category: Chuang, J L.]]		[[Category: Chuang, J L.]]

OCA at 12:08, 1 January 2014

OCA — Wed, 01 Jan 2014 12:08:18 GMT

←Older revision		Revision as of 12:08, 1 January 2014
Line 1:		Line 1:
-	~~'''Unreleased~~ structure~~'''~~	+	{{STRUCTURE_4mp2\| PDB=4mp2 \| SCENE= }}
		+	===Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1===
		+	{{ABSTRACT_PUBMED_24356970}}

-	~~The entry 4mp2 is ON HOLD~~ ~~until Paper Publication~~	+	==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>

-	~~Authors~~: ~~Gui, W.J., Tso, S.C., Chuang, J.L., Wu, C.Y., Qi, X., Tambar, U.K., Wynn, R~~.M.~~, Chuang, D~~.T.	+	==About this Structure==
		+	[[4mp2]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MP2 OCA].

-	~~Description~~: ~~Crystal structure of pyruvate dehydrogenase~~ kinase ~~isoform 2 in~~ complex ~~with~~ inhibitor ~~PA1~~	+	==Reference==
		+	<ref group="xtra">PMID:024356970</ref><references group="xtra"/><references/>
		+	[[Category: Chuang, D T.]]
		+	[[Category: Chuang, J L.]]
		+	[[Category: Gui, W J.]]
		+	[[Category: Qi, X.]]
		+	[[Category: Tambar, U K.]]
		+	[[Category: Tso, S C.]]
		+	[[Category: Wu, C Y.]]
		+	[[Category: Wynn, R M.]]
		+	[[Category: Bergerat nucleotide-binding fold]]
		+	[[Category: Cancer]]
		+	[[Category: Ghkl protein kinase]]
		+	[[Category: Hepatic steatosis]]
		+	[[Category: Impaired glucose oxidation]]
		+	[[Category: Mitochondrial protein kinase]]
		+	[[Category: Protein kinase]]
		+	[[Category: Pyruvate dehydrogenase complex]]
		+	[[Category: Transferase-transferase inhibitor complex]]
		+	[[Category: Type 2 diabetes]]

OCA at 07:39, 29 September 2013

OCA — Sun, 29 Sep 2013 07:39:47 GMT

←Older revision		Revision as of 07:39, 29 September 2013
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 4mp2 is ON HOLD	+	The entry 4mp2 is ON HOLD until Paper Publication

-	Authors: Gui, W.J., Tso, S.C., Chuang, J.L., Wu, C.Y., Qi, X., Tambar, U.K., Wynn, R. M., Chuang, D. T.	+	Authors: Gui, W.J., Tso, S.C., Chuang, J.L., Wu, C.Y., Qi, X., Tambar, U.K., Wynn, R.M., Chuang, D.T.

	Description: Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1		Description: Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1

OCA: Protected "4mp2" [edit=sysop:move=sysop]

OCA — Fri, 20 Sep 2013 03:45:28 GMT

Protected "4mp2" [edit=sysop:move=sysop]

←Older revision

Revision as of 03:45, 20 September 2013

OCA: New page: '''Unreleased structure''' The entry 4mp2 is ON HOLD Authors: Gui, W.J., Tso, S.C., Chuang, J.L., Wu, C.Y., Qi, X., Tambar, U.K., Wynn, R. M., Chuang, D. T. Description: Crystal struct...

OCA — Fri, 20 Sep 2013 03:45:27 GMT

New page: '''Unreleased structure''' The entry 4mp2 is ON HOLD Authors: Gui, W.J., Tso, S.C., Chuang, J.L., Wu, C.Y., Qi, X., Tambar, U.K., Wynn, R. M., Chuang, D. T. Description: Crystal struct...

New page

'''Unreleased structure'''

The entry 4mp2 is ON HOLD

Authors: Gui, W.J., Tso, S.C., Chuang, J.L., Wu, C.Y., Qi, X., Tambar, U.K., Wynn, R. M., Chuang, D. T.

Description: Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1