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| | ==Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1== | | ==Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PA1== |
| - | <StructureSection load='4mp2' size='340' side='right' caption='[[4mp2]], [[Resolution|resolution]] 1.75Å' scene=''> | + | <StructureSection load='4mp2' size='340' side='right'caption='[[4mp2]], [[Resolution|resolution]] 1.75Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4mp2]] 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=4MP2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MP2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4mp2]] 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=4MP2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MP2 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PV1:(5-BROMO-2,4-DIHYDROXYPHENYL)(1,3-DIHYDRO-2H-ISOINDOL-2-YL)METHANONE'>PV1</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PV1:(5-BROMO-2,4-DIHYDROXYPHENYL)(1,3-DIHYDRO-2H-ISOINDOL-2-YL)METHANONE'>PV1</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mp7|4mp7]], [[4mpc|4mpc]], [[4mpe|4mpe]]</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=4mp2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mp2 OCA], [https://pdbe.org/4mp2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mp2 RCSB], [https://www.ebi.ac.uk/pdbsum/4mp2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mp2 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDK2, PDHK2 ([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='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=4mp2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mp2 OCA], [http://pdbe.org/4mp2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mp2 RCSB], [http://www.ebi.ac.uk/pdbsum/4mp2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mp2 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Chuang, D T]] | + | [[Category: Large Structures]] |
| - | [[Category: Chuang, J L]] | + | [[Category: Chuang DT]] |
| - | [[Category: Gui, W J]] | + | [[Category: Chuang JL]] |
| - | [[Category: Qi, X]] | + | [[Category: Gui WJ]] |
| - | [[Category: Tambar, U K]] | + | [[Category: Qi X]] |
| - | [[Category: Tso, S C]] | + | [[Category: Tambar UK]] |
| - | [[Category: Wu, C Y]] | + | [[Category: Tso SC]] |
| - | [[Category: Wynn, R M]] | + | [[Category: Wu CY]] |
| - | [[Category: Bergerat nucleotide-binding fold]]
| + | [[Category: Wynn RM]] |
| - | [[Category: Cancer]]
| + | |
| - | [[Category: Ghkl protein kinase]]
| + | |
| - | [[Category: Hepatic steatosis]]
| + | |
| - | [[Category: Impaired glucose oxidation]]
| + | |
| - | [[Category: Mitochondrial protein kinase]]
| + | |
| - | [[Category: Protein kinase]]
| + | |
| - | [[Category: Pyruvate dehydrogenase complex]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| - | [[Category: Type 2 diabetes]]
| + | |
| 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]
Publication Abstract from PubMed
Pyruvate dehydrogenase kinase isoforms (PDKs 1 - 4) negatively regulate activity of the mitochondrial pyruvate dehydrogenase complex (PDC) by reversible phosphorylation. PDK isoforms are up-regulated in obesity, diabetes, heart failure and cancer and are potential therapeutic targets for these important human diseases. Here, we employed structure-guided design to convert a known Hsp90 inhibitor to a series of highly specific PDK inhibitors, based on structural conservation in the ATP-binding pocket. The key step involved the substitution of a carbonyl group in the parent compound with a sulfonyl in the PDK inhibitors. The final compound of this series, 2-[(2,4-dihydroxyphenyl)sulfonyl] isoindoline-4,6-diol, designated PS10, inhibits all four PDK isoforms with IC50 = 0.8 muM for PDK2. The administration of PS10 (70 mg/kg) to diet-induced obese mice significantly augments PDC activity with reduced phosphorylation in different tissues. Prolonged PS10 treatments result in improved glucose tolerance and notably lessened hepatic steatosis in the mouse model. The results support the pharmacological approach of targeting PDK to control both glucose and fat levels in obesity and type 2 diabetes.
Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket.,Tso SC, Qi X, Gui WJ, Wu CY, Chuang JL, Wernstedt-Asterholm I, Morlock LK, Owens KR, Scherer PE, Williams NS, Tambar UK, Wynn RM, Chuang DT J Biol Chem. 2013 Dec 19. PMID:24356970[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
- ↑ Tso SC, Qi X, Gui WJ, Wu CY, Chuang JL, Wernstedt-Asterholm I, Morlock LK, Owens KR, Scherer PE, Williams NS, Tambar UK, Wynn RM, Chuang DT. Structure-guided Development of Specific Pyruvate Dehydrogenase Kinase Inhibitors Targeting the ATP-binding Pocket. J Biol Chem. 2013 Dec 19. PMID:24356970 doi:http://dx.doi.org/10.1074/jbc.M113.533885
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