2q8h

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[[Image:2q8h.gif|left|200px]]
 
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==Structure of pyruvate dehydrogenase kinase isoform 1 in complex with dichloroacetate (DCA)==
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The line below this paragraph, containing "STRUCTURE_2q8h", creates the "Structure Box" on the page.
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<StructureSection load='2q8h' size='340' side='right'caption='[[2q8h]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[2q8h]] 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=2Q8H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Q8H FirstGlance]. <br>
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or leave the SCENE parameter empty for the default display.
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=K:POTASSIUM+ION'>K</scene>, <scene name='pdbligand=TF4:DICHLORO-ACETIC+ACID'>TF4</scene></td></tr>
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{{STRUCTURE_2q8h| PDB=2q8h | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2q8h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8h OCA], [https://pdbe.org/2q8h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2q8h RCSB], [https://www.ebi.ac.uk/pdbsum/2q8h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2q8h ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/q8/2q8h_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=2q8h ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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'''Structure of pyruvate dehydrogenase kinase isoform 1 in complex with dichloroacetate (DCA)'''
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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>
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==Overview==
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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.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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2Q8H is a [[Single protein]] structure of 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=2Q8H OCA].
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</div>
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<div class="pdbe-citations 2q8h" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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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:[http://www.ncbi.nlm.nih.gov/pubmed/17683942 17683942]
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*[[Pyruvate dehydrogenase kinase|Pyruvate dehydrogenase kinase]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Chuang, D T.]]
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[[Category: Chuang DT]]
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[[Category: Chuang, J L.]]
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[[Category: Chuang JL]]
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[[Category: Kato, M.]]
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[[Category: Kato M]]
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[[Category: Li, J.]]
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[[Category: Li J]]
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[[Category: Dichroloacetate]]
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[[Category: Ghkl atpase/kinase family]]
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[[Category: Mitochondrial kinase]]
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[[Category: Pyruvate dehydrogenase complex]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 14:32:02 2008''
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Current revision

Structure of pyruvate dehydrogenase kinase isoform 1 in complex with dichloroacetate (DCA)

PDB ID 2q8h

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