3d2r

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{{Seed}}
 
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[[Image:3d2r.png|left|200px]]
 
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==Crystal structure of pyruvate dehydrogenase kinase isoform 4 in complex with ADP==
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The line below this paragraph, containing "STRUCTURE_3d2r", creates the "Structure Box" on the page.
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<StructureSection load='3d2r' size='340' side='right'caption='[[3d2r]], [[Resolution|resolution]] 2.03&Aring;' scene=''>
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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'>[[3d2r]] is a 2 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=3D2R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3D2R 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]] 2.03&#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=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
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{{STRUCTURE_3d2r| PDB=3d2r | 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=3d2r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d2r OCA], [https://pdbe.org/3d2r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3d2r RCSB], [https://www.ebi.ac.uk/pdbsum/3d2r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3d2r ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/PDK4_HUMAN PDK4_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. Inhibition of pyruvate dehydrogenase decreases glucose utilization and increases fat metabolism in response to prolonged fasting and starvation. Plays an important role in maintaining normal blood glucose levels under starvation, and is involved in the insulin signaling cascade. 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. In the fed state, mediates cellular responses to glucose levels and to a high-fat diet. Regulates both fatty acid oxidation and de novo fatty acid biosynthesis. Plays a role in the generation of reactive oxygen species. Protects detached epithelial cells against anoikis. Plays a role in cell proliferation via its role in regulating carbohydrate and fatty acid metabolism.<ref>PMID:15955060</ref> <ref>PMID:21852536</ref> <ref>PMID:21816445</ref> <ref>PMID:18658136</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/d2/3d2r_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=3d2r 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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Human pyruvate dehydrogenase complex (PDC) is down-regulated by pyruvate dehydrogenase kinase (PDK) isoforms 1-4. PDK4 is overexpressed in skeletal muscle in type 2 diabetes, resulting in impaired glucose utilization. Here we show that human PDK4 has robust core-free basal activity, which is considerably higher than activity levels of other PDK isoforms stimulated by the PDC core. PDK4 binds the L3 lipoyl domain, but its activity is not significantly stimulated by any individual lipoyl domains or the core of PDC. The 2.0-A crystal structures of the PDK4 dimer with bound ADP reveal an open conformation with a wider active-site cleft, compared with that in the closed conformation epitomized by the PDK2-ADP structure. The open conformation in PDK4 shows partially ordered C-terminal cross-tails, in which the conserved DW (Asp(394)-Trp(395)) motif from one subunit anchors to the N-terminal domain of the other subunit. The open conformation fosters a reduced binding affinity for ADP, facilitating the efficient removal of product inhibition by this nucleotide. Alteration or deletion of the DW-motif disrupts the C-terminal cross-tail anchor, resulting in the closed conformation and the nearly complete inactivation of PDK4. Fluorescence quenching and enzyme activity data suggest that compounds AZD7545 and dichloroacetate lock PDK4 in the open and the closed conformational states, respectively. We propose that PDK4 with bound ADP exists in equilibrium between the open and the closed conformations. The favored metastable open conformation is responsible for the robust basal activity of PDK4 in the absence of the PDC core.
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===Crystal structure of pyruvate dehydrogenase kinase isoform 4 in complex with ADP===
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Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity.,Wynn RM, Kato M, Chuang JL, Tso SC, Li J, Chuang DT J Biol Chem. 2008 Sep 12;283(37):25305-15. Epub 2008 Jul 24. PMID:18658136<ref>PMID:18658136</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 3d2r" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_18658136}}, adds the Publication Abstract to the page
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*[[Pyruvate dehydrogenase kinase|Pyruvate dehydrogenase kinase]]
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(as it appears on PubMed at http://www.pubmed.gov), where 18658136 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_18658136}}
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__TOC__
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</StructureSection>
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==About this Structure==
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3D2R 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=3D2R OCA].
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==Reference==
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Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity., Wynn RM, Kato M, Chuang JL, Tso SC, Li J, Chuang DT, J Biol Chem. 2008 Sep 12;283(37):25305-15. Epub 2008 Jul 24. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18658136 18658136]
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[[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, L C.]]
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[[Category: Chuang LC]]
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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: Tso, S C.]]
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[[Category: Tso S-C]]
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[[Category: Wynn, R M.]]
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[[Category: Wynn RM]]
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[[Category: Carbohydrate metabolism]]
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[[Category: Ghkl superfamily]]
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[[Category: Glucose metabolism]]
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[[Category: Homodimer]]
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[[Category: Kinase]]
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[[Category: Mitochondrion]]
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[[Category: Phosphoprotein]]
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[[Category: Polymorphism]]
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[[Category: Protein-nucleotide complex]]
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[[Category: Transferase]]
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[[Category: Transit peptide]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Sep 24 09:18:07 2008''
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Current revision

Crystal structure of pyruvate dehydrogenase kinase isoform 4 in complex with ADP

PDB ID 3d2r

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