2q8g

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(New page: 200px<br /> <applet load="2q8g" size="450" color="white" frame="true" align="right" spinBox="true" caption="2q8g, resolution 1.900&Aring;" /> '''Structure of pyruv...)
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[[Image:2q8g.gif|left|200px]]<br />
 
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<applet load="2q8g" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2q8g, resolution 1.900&Aring;" />
 
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'''Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545'''<br />
 
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==Overview==
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==Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545==
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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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<StructureSection load='2q8g' size='340' side='right'caption='[[2q8g]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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== Structural highlights ==
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<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>
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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]] 1.9&#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=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>
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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=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>
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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/q8/2q8g_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=2q8g ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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2Q8G is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with K and AZX as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2Q8G OCA].
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*[[Pyruvate dehydrogenase kinase|Pyruvate dehydrogenase kinase]]
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== References ==
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==Reference==
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<references/>
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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://ispc.weizmann.ac.il//pmbin/getpm?pmid=17683942 17683942]
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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: [Pyruvate dehydrogenase (acetyl-transferring)] kinase]]
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[[Category: Chuang DT]]
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[[Category: Chuang, D.T.]]
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[[Category: Chuang JL]]
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[[Category: Chuang, J.L.]]
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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: AZX]]
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[[Category: K]]
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[[Category: ghkl atpase/kinase family]]
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[[Category: glucose-lowering drug azd7545]]
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[[Category: mitochondrial kinase]]
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[[Category: pyruvate dehydrogenase complex]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 23:31:08 2007''
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Current revision

Structure of pyruvate dehydrogenase kinase isoform 1 in complex with glucose-lowering drug AZD7545

PDB ID 2q8g

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