2q8g - Revision history

OCA at 13:54, 13 March 2024

OCA — Wed, 13 Mar 2024 13:54:02 GMT

←Older revision		Revision as of 13:54, 13 March 2024
Line 20:		Line 20:
	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2q8g ConSurf].		</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2q8g ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Pyruvate dehydrogenase kinase (PDK) isoforms are molecular switches that downregulate the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation in mitochondria. We have determined structures of human PDK1 or PDK3 bound to the inhibitors AZD7545, dichloroacetate (DCA), and radicicol. We show that the trifluoromethylpropanamide end of AZD7545 projects into the lipoyl-binding pocket of PDK1. This interaction results in inhibition of PDK1 and PDK3 activities by aborting kinase binding to the PDC scaffold. Paradoxically, AZD7545 at saturating concentrations robustly increases scaffold-free PDK3 activity, similar to the inner lipoyl domain. Good DCA density is present in the helix bundle in the N-terminal domain of PDK1. Bound DCA promotes local conformational changes that are communicated to both nucleotide-binding and lipoyl-binding pockets of PDK1, leading to the inactivation of kinase activity. Finally, radicicol inhibits kinase activity by binding directly to the ATP-binding pocket of PDK3, similar to Hsp90 and Topo VI from the same ATPase/kinase superfamily.
-
-	Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol.,Kato M, Li J, Chuang JL, Chuang DT Structure. 2007 Aug;15(8):992-1004. Epub 2007 Aug 2. PMID:17683942<ref>PMID:17683942</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 2q8g" style="background-color:#fffaf0;"></div>

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

OCA at 11:25, 30 August 2023

OCA — Wed, 30 Aug 2023 11:25:08 GMT

←Older revision		Revision as of 11:25, 30 August 2023
Line 3:		Line 3:
	<StructureSection load='2q8g' size='340' side='right'caption='[[2q8g]], [[Resolution\|resolution]] 1.90Å' scene=''>		<StructureSection load='2q8g' size='340' side='right'caption='[[2q8g]], [[Resolution\|resolution]] 1.90Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2q8g]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Q8G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Q8G FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2q8g]] 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=2Q8G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Q8G FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AZX:4-[(3-CHLORO-4-{[(2R)-3,3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANOYL]AMINO}PHENYL)SULFONYL]-N,N-DIMETHYLBENZAMIDE'>AZX</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</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]] 1.9Å</td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2q8f\|2q8f]], [[2q8h\|2q8h]], [[2q8i\|2q8i]]</div></td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AZX:4-[(3-CHLORO-4-{[(2R)-3,3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANOYL]AMINO}PHENYL)SULFONYL]-N,N-DIMETHYLBENZAMIDE'>AZX</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDK1 ([https://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'>[https://en.wikipedia.org/wiki/[Pyruvate_dehydrogenase_(acetyl-transferring)]_kinase [Pyruvate dehydrogenase (acetyl-transferring)] kinase], with EC number [https://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=2q8g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8g OCA], [https://pdbe.org/2q8g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2q8g RCSB], [https://www.ebi.ac.uk/pdbsum/2q8g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2q8g 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=2q8g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8g OCA], [https://pdbe.org/2q8g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2q8g RCSB], [https://www.ebi.ac.uk/pdbsum/2q8g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2q8g ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/PDK1_HUMAN PDK1_HUMAN]] Serine/threonine kinase that plays a key role in 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. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress.<ref>PMID:7499431</ref> <ref>PMID:18541534</ref> <ref>PMID:22195962</ref> <ref>PMID:17683942</ref>	+	[https://www.uniprot.org/uniprot/PDK1_HUMAN PDK1_HUMAN] Serine/threonine kinase that plays a key role in 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. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress.<ref>PMID:7499431</ref> <ref>PMID:18541534</ref> <ref>PMID:22195962</ref> <ref>PMID:17683942</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
Line 38:		Line 36:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Chuang~~, D T~~]]	+	[[Category: Chuang DT]]
-	[[Category: Chuang~~, J L~~]]	+	[[Category: Chuang JL]]
-	[[Category: Kato, M]]	+	[[Category: Kato M]]
-	[[Category: Li, J]]	+	[[Category: Li J]]
-	~~[[Category: Ghkl atpase/kinase family]]~~	+
-	~~[[Category: Glucose-lowering drug azd7545]]~~	+
-	~~[[Category: Mitochondrial kinase]]~~	+
-	~~[[Category: Pyruvate dehydrogenase complex]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 08:12, 25 June 2021

OCA — Fri, 25 Jun 2021 08:12:01 GMT

←Older revision		Revision as of 08:12, 25 June 2021
Line 1:		Line 1:

	==Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545==		==Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545==
-	<StructureSection load='2q8g' size='340' side='right' caption='[[2q8g]], [[Resolution\|resolution]] 1.90Å' scene=''>	+	<StructureSection load='2q8g' size='340' side='right'caption='[[2q8g]], [[Resolution\|resolution]] 1.90Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2q8g]] 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=2Q8G OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=2Q8G FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2q8g]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Q8G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Q8G FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AZX:4-[(3-CHLORO-4-{[(2R)-3,3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANOYL]AMINO}PHENYL)SULFONYL]-N,N-DIMETHYLBENZAMIDE'>AZX</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AZX:4-[(3-CHLORO-4-{[(2R)-3,3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANOYL]AMINO}PHENYL)SULFONYL]-N,N-DIMETHYLBENZAMIDE'>AZX</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>
-	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2q8f\|2q8f]], [[2q8h\|2q8h]], [[2q8i\|2q8i]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2q8f\|2q8f]], [[2q8h\|2q8h]], [[2q8i\|2q8i]]</div></td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDK1 ([~~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">PDK1 ([https://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'>[https://en.wikipedia.org/wiki/[Pyruvate_dehydrogenase_(acetyl-transferring)]_kinase [Pyruvate dehydrogenase (acetyl-transferring)] kinase], with EC number [https://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=2q8g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8g OCA], [~~http~~://pdbe.org/2q8g PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=2q8g RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/2q8g PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=2q8g 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=2q8g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8g OCA], [https://pdbe.org/2q8g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2q8g RCSB], [https://www.ebi.ac.uk/pdbsum/2q8g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2q8g ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[~~http~~://www.uniprot.org/uniprot/PDK1_HUMAN PDK1_HUMAN]] Serine/threonine kinase that plays a key role in 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. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress.<ref>PMID:7499431</ref> <ref>PMID:18541534</ref> <ref>PMID:22195962</ref> <ref>PMID:17683942</ref>	+	[[https://www.uniprot.org/uniprot/PDK1_HUMAN PDK1_HUMAN]] Serine/threonine kinase that plays a key role in 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. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress.<ref>PMID:7499431</ref> <ref>PMID:18541534</ref> <ref>PMID:22195962</ref> <ref>PMID:17683942</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
	Check<jmol>		Check<jmol>
	<jmolCheckbox>		<jmolCheckbox>
-	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/q8/2q8g_consurf.spt"</scriptWhenChecked>	+	<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/q8/2q8g_consurf.spt"</scriptWhenChecked>
	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>		<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
Line 39:		Line 39:
	</StructureSection>		</StructureSection>
	[[Category: Human]]		[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Chuang, D T]]		[[Category: Chuang, D T]]
	[[Category: Chuang, J L]]		[[Category: Chuang, J L]]

OCA at 09:41, 18 October 2017

OCA — Wed, 18 Oct 2017 09:41:09 GMT

←Older revision		Revision as of 09:41, 18 October 2017
Line 1:		Line 1:
		+
	==Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545==		==Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545==
	<StructureSection load='2q8g' size='340' side='right' caption='[[2q8g]], [[Resolution\|resolution]] 1.90Å' scene=''>		<StructureSection load='2q8g' size='340' side='right' caption='[[2q8g]], [[Resolution\|resolution]] 1.90Å' scene=''>
Line 7:		Line 8:
	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDK1 ([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">PDK1 ([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=2q8g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8g OCA], [http://pdbe.org/2q8g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2q8g RCSB], [http://www.ebi.ac.uk/pdbsum/2q8g 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=2q8g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8g OCA], [http://pdbe.org/2q8g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2q8g RCSB], [http://www.ebi.ac.uk/pdbsum/2q8g PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2q8g ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==

OCA at 20:27, 9 February 2016

OCA — Tue, 09 Feb 2016 20:27:23 GMT

←Older revision		Revision as of 20:27, 9 February 2016
Line 19:		Line 19:
	<text>to colour the structure by Evolutionary Conservation</text>		<text>to colour the structure by Evolutionary Conservation</text>
	</jmolCheckbox>		</jmolCheckbox>
-	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/~~chain_selection~~.php?pdb_ID=~~2ata~~ ConSurf].	+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2q8g ConSurf].
	<div style="clear:both"></div>		<div style="clear:both"></div>
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">

OCA at 01:45, 11 September 2015

OCA — Fri, 11 Sep 2015 01:45:02 GMT

←Older revision		Revision as of 01:45, 11 September 2015
Line 2:		Line 2:
	<StructureSection load='2q8g' size='340' side='right' caption='[[2q8g]], [[Resolution\|resolution]] 1.90Å' scene=''>		<StructureSection load='2q8g' size='340' side='right' caption='[[2q8g]], [[Resolution\|resolution]] 1.90Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[2q8g]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/~~Homo_sapiens Homo sapiens~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Q8G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Q8G FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[2q8g]] 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=2Q8G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Q8G FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AZX:4-[(3-CHLORO-4-{[(2R)-3,3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANOYL]AMINO}PHENYL)SULFONYL]-N,N-DIMETHYLBENZAMIDE'>AZX</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AZX:4-[(3-CHLORO-4-{[(2R)-3,3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANOYL]AMINO}PHENYL)SULFONYL]-N,N-DIMETHYLBENZAMIDE'>AZX</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2q8f\|2q8f]], [[2q8h\|2q8h]], [[2q8i\|2q8i]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2q8f\|2q8f]], [[2q8h\|2q8h]], [[2q8i\|2q8i]]</td></tr>
-	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 ~~Homo sapiens~~])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDK1 ([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=2q8g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8g OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2q8g RCSB], [http://www.ebi.ac.uk/pdbsum/2q8g 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=2q8g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8g OCA], [http://pdbe.org/2q8g PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2q8g RCSB], [http://www.ebi.ac.uk/pdbsum/2q8g PDBsum]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
Line 29:		Line 29:
	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 2q8g" style="background-color:#fffaf0;"></div>

	==See Also==		==See Also==
Line 36:		Line 37:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Homo sapiens~~]]	+	[[Category: Human]]
	[[Category: Chuang, D T]]		[[Category: Chuang, D T]]
	[[Category: Chuang, J L]]		[[Category: Chuang, J L]]

OCA at 09:20, 25 December 2014

OCA — Thu, 25 Dec 2014 09:20:10 GMT

←Older revision		Revision as of 09:20, 25 December 2014
Line 3:		Line 3:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[2q8g]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Q8G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Q8G FirstGlance]. <br>		<table><tr><td colspan='2'>[[2q8g]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Q8G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Q8G FirstGlance]. <br>
-	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AZX:4-[(3-CHLORO-4-{[(2R)-3,3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANOYL]AMINO}PHENYL)SULFONYL]-N,N-DIMETHYLBENZAMIDE'>AZX</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene><br>	+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AZX:4-[(3-CHLORO-4-{[(2R)-3,3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANOYL]AMINO}PHENYL)SULFONYL]-N,N-DIMETHYLBENZAMIDE'>AZX</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>
-	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2q8f\|2q8f]], [[2q8h\|2q8h]], [[2q8i\|2q8i]]</td></tr>	+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2q8f\|2q8f]], [[2q8h\|2q8h]], [[2q8i\|2q8i]]</td></tr>
-	<tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr>	+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=2q8g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8g OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2q8g RCSB], [http://www.ebi.ac.uk/pdbsum/2q8g 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=2q8g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8g OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2q8g RCSB], [http://www.ebi.ac.uk/pdbsum/2q8g PDBsum]</span></td></tr>
-	<table>	+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/PDK1_HUMAN PDK1_HUMAN]] Serine/threonine kinase that plays a key role in 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. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress.<ref>PMID:7499431</ref> <ref>PMID:18541534</ref> <ref>PMID:22195962</ref> <ref>PMID:17683942</ref>
	== Evolutionary Conservation ==		== Evolutionary Conservation ==
	[[Image:Consurf_key_small.gif\|200px\|right]]		[[Image:Consurf_key_small.gif\|200px\|right]]
Line 35:		Line 37:
	</StructureSection>		</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
-	[[Category: Chuang, D T.]]	+	[[Category: Chuang, D T]]
-	[[Category: Chuang, J L.]]	+	[[Category: Chuang, J L]]
-	[[Category: Kato, M.]]	+	[[Category: Kato, M]]
-	[[Category: Li, J.]]	+	[[Category: Li, J]]
	[[Category: Ghkl atpase/kinase family]]		[[Category: Ghkl atpase/kinase family]]
	[[Category: Glucose-lowering drug azd7545]]		[[Category: Glucose-lowering drug azd7545]]

OCA at 18:11, 30 September 2014

OCA — Tue, 30 Sep 2014 18:11:26 GMT

←Older revision		Revision as of 18:11, 30 September 2014
Line 1:		Line 1:
-	~~{{STRUCTURE_2q8g\| PDB=2q8g \| SCENE= }}~~	+	==Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545==
-	===Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545===	+	<StructureSection load='2q8g' size='340' side='right' caption='[[2q8g]], [[Resolution\|resolution]] 1.90Å' scene=''>
-	{~~{ABSTRACT_PUBMED_17683942}~~}	+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[2q8g]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Q8G OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Q8G FirstGlance]. <br>
		+	</td></tr><tr><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AZX:4-[(3-CHLORO-4-{[(2R)-3,3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANOYL]AMINO}PHENYL)SULFONYL]-N,N-DIMETHYLBENZAMIDE'>AZX</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene><br>
		+	<tr><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[2q8f\|2q8f]], [[2q8h\|2q8h]], [[2q8i\|2q8i]]</td></tr>
		+	<tr><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">PDK1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=2q8g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8g OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2q8g RCSB], [http://www.ebi.ac.uk/pdbsum/2q8g PDBsum]</span></td></tr>
		+	<table>
		+	== Evolutionary Conservation ==
		+	[[Image:Consurf_key_small.gif\|200px\|right]]
		+	Check<jmol>
		+	<jmolCheckbox>
		+	<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/q8/2q8g_consurf.spt"</scriptWhenChecked>
		+	<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
		+	<text>to colour the structure by Evolutionary Conservation</text>
		+	</jmolCheckbox>
		+	</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary\|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/chain_selection.php?pdb_ID=2ata ConSurf].
		+	<div style="clear:both"></div>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Pyruvate dehydrogenase kinase (PDK) isoforms are molecular switches that downregulate the pyruvate dehydrogenase complex (PDC) by reversible phosphorylation in mitochondria. We have determined structures of human PDK1 or PDK3 bound to the inhibitors AZD7545, dichloroacetate (DCA), and radicicol. We show that the trifluoromethylpropanamide end of AZD7545 projects into the lipoyl-binding pocket of PDK1. This interaction results in inhibition of PDK1 and PDK3 activities by aborting kinase binding to the PDC scaffold. Paradoxically, AZD7545 at saturating concentrations robustly increases scaffold-free PDK3 activity, similar to the inner lipoyl domain. Good DCA density is present in the helix bundle in the N-terminal domain of PDK1. Bound DCA promotes local conformational changes that are communicated to both nucleotide-binding and lipoyl-binding pockets of PDK1, leading to the inactivation of kinase activity. Finally, radicicol inhibits kinase activity by binding directly to the ATP-binding pocket of PDK3, similar to Hsp90 and Topo VI from the same ATPase/kinase superfamily.

-	~~==About this~~ Structure==	+	Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol.,Kato M, Li J, Chuang JL, Chuang DT Structure. 2007 Aug;15(8):992-1004. Epub 2007 Aug 2. PMID:17683942<ref>PMID:17683942</ref>
-	~~[[2q8g]] is a 1 chain structure with sequence from [http~~:~~//en~~.~~wikipedia.org/wiki/Homo_sapiens Homo sapiens]~~. ~~Full crystallographic information is available from [http~~://~~oca~~.~~weizmann~~.ac.il/~~oca-bin/ocashort?id=2Q8G OCA].~~	+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>

	==See Also==		==See Also==
	*[[Pyruvate dehydrogenase kinase\|Pyruvate dehydrogenase kinase]]		*[[Pyruvate dehydrogenase kinase\|Pyruvate dehydrogenase kinase]]
-		+	== References ==
-	==~~Reference~~==	+	<references/>
-	<~~ref group="xtra">PMID:017683942<~~/~~ref~~><~~references group="xtra"~~/>	+	__TOC__
		+	</StructureSection>
	[[Category: Homo sapiens]]		[[Category: Homo sapiens]]
	[[Category: Chuang, D T.]]		[[Category: Chuang, D T.]]

OCA at 09:18, 11 March 2013

OCA — Mon, 11 Mar 2013 09:18:13 GMT

←Older revision		Revision as of 09:18, 11 March 2013
Line 1:		Line 1:
-	[[Image:2q8g.png\|left\|200px]]
-
	{{STRUCTURE_2q8g\| PDB=2q8g \| SCENE= }}		{{STRUCTURE_2q8g\| PDB=2q8g \| SCENE= }}
-
	===Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545===		===Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545===
-
	{{ABSTRACT_PUBMED_17683942}}		{{ABSTRACT_PUBMED_17683942}}

OCA: Protected "2q8g" [edit=sysop:move=sysop]

OCA — Mon, 07 Jan 2013 20:49:11 GMT

Protected "2q8g" [edit=sysop:move=sysop]

←Older revision

Revision as of 20:49, 7 January 2013