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| | <StructureSection load='2bu2' size='340' side='right'caption='[[2bu2]], [[Resolution|resolution]] 2.40Å' scene=''> | | <StructureSection load='2bu2' size='340' side='right'caption='[[2bu2]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2bu2]] 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=2BU2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BU2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2bu2]] 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=2BU2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BU2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TF1:4-({(2R,5S)-2,5-DIMETHYL-4-[(2R)-3,3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANOYL]PIPERAZIN-1-YL}CARBONYL)BENZONITRILE'>TF1</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]] 2.4Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[2btz|2btz]], [[2bu5|2bu5]], [[2bu6|2bu6]], [[2bu7|2bu7]], [[2bu8|2bu8]]</div></td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=TF1:4-({(2R,5S)-2,5-DIMETHYL-4-[(2R)-3,3,3-TRIFLUORO-2-HYDROXY-2-METHYLPROPANOYL]PIPERAZIN-1-YL}CARBONYL)BENZONITRILE'>TF1</scene></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=2bu2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bu2 OCA], [https://pdbe.org/2bu2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2bu2 RCSB], [https://www.ebi.ac.uk/pdbsum/2bu2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2bu2 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=2bu2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bu2 OCA], [https://pdbe.org/2bu2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2bu2 RCSB], [https://www.ebi.ac.uk/pdbsum/2bu2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2bu2 ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | + | == 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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Brown, D G]] | + | [[Category: Brown DG]] |
| - | [[Category: Bungay, P J]] | + | [[Category: Bungay PJ]] |
| - | [[Category: Kasten, S A]] | + | [[Category: Kasten SA]] |
| - | [[Category: Knoechel, T R]] | + | [[Category: Knoechel TR]] |
| - | [[Category: Phillips, C]] | + | [[Category: Phillips C]] |
| - | [[Category: Robinson, C M]] | + | [[Category: Robinson CM]] |
| - | [[Category: Roche, T E]] | + | [[Category: Roche TE]] |
| - | [[Category: Taylor, W]] | + | [[Category: Taylor W]] |
| - | [[Category: Tucker, A D]] | + | [[Category: Tucker AD]] |
| - | [[Category: Ghkl motif regulation]]
| + | |
| - | [[Category: Transferase]]
| + | |
| Structural highlights
Function
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.[1] [2] [3] [4] [5] [6]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Pyruvate dehydrogenase kinase (PDHK) regulates the activity of the pyruvate dehydrogenase multienzyme complex. PDHK inhibition provides a route for therapeutic intervention in diabetes and cardiovascular disorders. We report crystal structures of human PDHK isozyme 2 complexed with physiological and synthetic ligands. Several of the PDHK2 structures disclosed have C-terminal cross arms that span a large trough region between the N-terminal regulatory (R) domains of the PDHK2 dimers. The structures containing bound ATP and ADP demonstrate variation in the conformation of the active site lid, residues 316-321, which enclose the nucleotide beta and gamma phosphates at the active site in the C-terminal catalytic domain. We have identified three novel ligand binding sites located in the R domain of PDHK2. Dichloroacetate (DCA) binds at the pyruvate binding site in the center of the R domain, which together with ADP, induces significant changes at the active site. Nov3r and AZ12 inhibitors bind at the lipoamide binding site that is located at one end of the R domain. Pfz3 (an allosteric inhibitor) binds in an extended site at the other end of the R domain. We conclude that the N-terminal domain of PDHK has a key regulatory function and propose that the different inhibitor classes act by discrete mechanisms. The structures we describe provide insights that can be used for structure-based design of PDHK inhibitors.
Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands.,Knoechel TR, Tucker AD, Robinson CM, Phillips C, Taylor W, Bungay PJ, Kasten SA, Roche TE, Brown DG Biochemistry. 2006 Jan 17;45(2):402-15. PMID:16401071[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Gudi R, Bowker-Kinley MM, Kedishvili NY, Zhao Y, Popov KM. Diversity of the pyruvate dehydrogenase kinase gene family in humans. J Biol Chem. 1995 Dec 1;270(48):28989-94. PMID:7499431
- ↑ Majer M, Popov KM, Harris RA, Bogardus C, Prochazka M. Insulin downregulates pyruvate dehydrogenase kinase (PDK) mRNA: potential mechanism contributing to increased lipid oxidation in insulin-resistant subjects. Mol Genet Metab. 1998 Oct;65(2):181-6. PMID:9787110 doi:http://dx.doi.org/10.1006/mgme.1998.2748
- ↑ Bonnet S, Archer SL, Allalunis-Turner J, Haromy A, Beaulieu C, Thompson R, Lee CT, Lopaschuk GD, Puttagunta L, Bonnet S, Harry G, Hashimoto K, Porter CJ, Andrade MA, Thebaud B, Michelakis ED. A mitochondria-K+ channel axis is suppressed in cancer and its normalization promotes apoptosis and inhibits cancer growth. Cancer Cell. 2007 Jan;11(1):37-51. PMID:17222789 doi:http://dx.doi.org/10.1016/j.ccr.2006.10.020
- ↑ Li J, Kato M, Chuang DT. Pivotal role of the C-terminal DW-motif in mediating inhibition of pyruvate dehydrogenase kinase 2 by dichloroacetate. J Biol Chem. 2009 Dec 4;284(49):34458-67. doi: 10.1074/jbc.M109.065557. Epub 2009, Oct 15. PMID:19833728 doi:http://dx.doi.org/10.1074/jbc.M109.065557
- ↑ Sun W, Chang SS, Fu Y, Liu Y, Califano JA. Chronic CSE treatment induces the growth of normal oral keratinocytes via PDK2 upregulation, increased glycolysis and HIF1alpha stabilization. PLoS One. 2011 Jan 19;6(1):e16207. doi: 10.1371/journal.pone.0016207. PMID:21283817 doi:http://dx.doi.org/10.1371/journal.pone.0016207
- ↑ Contractor T, Harris CR. p53 negatively regulates transcription of the pyruvate dehydrogenase kinase Pdk2. Cancer Res. 2012 Jan 15;72(2):560-7. doi: 10.1158/0008-5472.CAN-11-1215. Epub, 2011 Nov 28. PMID:22123926 doi:http://dx.doi.org/10.1158/0008-5472.CAN-11-1215
- ↑ Knoechel TR, Tucker AD, Robinson CM, Phillips C, Taylor W, Bungay PJ, Kasten SA, Roche TE, Brown DG. Regulatory roles of the N-terminal domain based on crystal structures of human pyruvate dehydrogenase kinase 2 containing physiological and synthetic ligands. Biochemistry. 2006 Jan 17;45(2):402-15. PMID:16401071 doi:10.1021/bi051402s
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