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2q8i

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Revision as of 09:41, 18 October 2017

Pyruvate dehydrogenase kinase isoform 3 in complex with antitumor drug radicicol

Structural highlights

2q8i is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , ,
Related:	2q8f, 2q8g, 2q8h
Gene:	PDK3 (HUMAN), DLAT, DLTA (HUMAN)
Activity:	[Pyruvate_dehydrogenase_(acetyl-transferring)_kinase [Pyruvate dehydrogenase (acetyl-transferring)] kinase], with EC number 2.7.11.2
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[ODP2_HUMAN] Note=Primary biliary cirrhosis is a chronic, progressive cholestatic liver disease characterized by the presence of antimitochondrial autoantibodies in patients' serum. It manifests with inflammatory obliteration of intra-hepatic bile duct, leading to liver cell damage and cirrhosis. Patients with primary biliary cirrhosis show autoantibodies against the E2 component of pyruvate dehydrogenase complex. Defects in DLAT are the cause of pyruvate dehydrogenase E2 deficiency (PDHE2 deficiency) [MIM:245348]; also known as lactic acidemia due to defect of E2 lipoyl transacetylase of the pyruvate dehydrogenase complex. Pyruvate dehydrogenase (PDH) deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. In this form of PDH deficiency episodic dystonia is the major neurological manifestation, with other more common features of pyruvate dehydrogenase deficiency, such as hypotonia and ataxia, being less prominent.

Function

[PDK3_HUMAN] Inhibits pyruvate dehydrogenase activity by phosphorylation of the E1 subunit PDHA1, and thereby regulates glucose metabolism and aerobic respiration. Can also phosphorylate PDHA2. Decreases glucose utilization and increases fat metabolism in response to prolonged fasting, and as adaptation to a high-fat diet. Plays a role in glucose homeostasis and in maintaining normal blood glucose levels in function of nutrient levels and under starvation. Plays a role in the generation of reactive oxygen species.^[1] ^[2] ^[3] ^[4] ^[5] ^[6] ^[7] [ODP2_HUMAN] The pyruvate dehydrogenase complex catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2), and thereby links the glycolytic pathway to the tricarboxylic cycle.

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 (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.

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^[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Baker JC, Yan X, Peng T, Kasten S, Roche TE. Marked differences between two isoforms of human pyruvate dehydrogenase kinase. J Biol Chem. 2000 May 26;275(21):15773-81. PMID:10748134 doi:10.1074/jbc.M909488199
↑ Korotchkina LG, Patel MS. Site specificity of four pyruvate dehydrogenase kinase isoenzymes toward the three phosphorylation sites of human pyruvate dehydrogenase. J Biol Chem. 2001 Oct 5;276(40):37223-9. Epub 2001 Aug 2. PMID:11486000 doi:10.1074/jbc.M103069200
↑ Korotchkina LG, Sidhu S, Patel MS. Characterization of testis-specific isoenzyme of human pyruvate dehydrogenase. J Biol Chem. 2006 Apr 7;281(14):9688-96. Epub 2006 Jan 25. PMID:16436377 doi:10.1074/jbc.M511481200
↑ Lu CW, Lin SC, Chen KF, Lai YY, Tsai SJ. Induction of pyruvate dehydrogenase kinase-3 by hypoxia-inducible factor-1 promotes metabolic switch and drug resistance. J Biol Chem. 2008 Oct 17;283(42):28106-14. doi: 10.1074/jbc.M803508200. Epub 2008, Aug 21. PMID:18718909 doi:10.1074/jbc.M803508200
↑ Kluza J, Corazao-Rozas P, Touil Y, Jendoubi M, Maire C, Guerreschi P, Jonneaux A, Ballot C, Balayssac S, Valable S, Corroyer-Dulmont A, Bernaudin M, Malet-Martino M, de Lassalle EM, Maboudou P, Formstecher P, Polakowska R, Mortier L, Marchetti P. Inactivation of the HIF-1alpha/PDK3 signaling axis drives melanoma toward mitochondrial oxidative metabolism and potentiates the therapeutic activity of pro-oxidants. Cancer Res. 2012 Oct 1;72(19):5035-47. doi: 10.1158/0008-5472.CAN-12-0979. Epub, 2012 Aug 3. PMID:22865452 doi:10.1158/0008-5472.CAN-12-0979
↑ Kato M, Chuang JL, Tso SC, Wynn RM, Chuang DT. Crystal structure of pyruvate dehydrogenase kinase 3 bound to lipoyl domain 2 of human pyruvate dehydrogenase complex. EMBO J. 2005 May 18;24(10):1763-74. Epub 2005 Apr 28. PMID:15861126
↑ Kato M, Li J, Chuang JL, Chuang DT. Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure. 2007 Aug;15(8):992-1004. Epub 2007 Aug 2. PMID:17683942 doi:10.1016/j.str.2007.07.001
↑ Kato M, Li J, Chuang JL, Chuang DT. Distinct structural mechanisms for inhibition of pyruvate dehydrogenase kinase isoforms by AZD7545, dichloroacetate, and radicicol. Structure. 2007 Aug;15(8):992-1004. Epub 2007 Aug 2. PMID:17683942 doi:10.1016/j.str.2007.07.001

1 Structural highlights
2 Disease
3 Function
4 Evolutionary Conservation
5 Publication Abstract from PubMed
6 See Also
7 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2q8i"

@@ Line 1: / Line 1: @@
 ==Pyruvate dehydrogenase kinase isoform 3 in complex with antitumor drug radicicol==
 <StructureSection load='2q8i' size='340' side='right' caption='[[2q8i]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
@@ Line 7: / Line 8: @@
 <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDK3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), DLAT, DLTA ([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=2q8i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8i OCA], [http://pdbe.org/2q8i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2q8i RCSB], [http://www.ebi.ac.uk/pdbsum/2q8i PDBsum]</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=2q8i FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2q8i OCA], [http://pdbe.org/2q8i PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2q8i RCSB], [http://www.ebi.ac.uk/pdbsum/2q8i PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2q8i ProSAT]</span></td></tr>
 </table>
 == Disease ==
@@ Line 21: / Line 22: @@
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
-</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/chain_selection.php?pdb_ID=2ata ConSurf].
+</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=2q8i ConSurf].
 <div style="clear:both"></div>
 <div style="background-color:#fffaf0;">

2q8i

From Proteopedia

Revision as of 09:41, 18 October 2017

Pyruvate dehydrogenase kinase isoform 3 in complex with antitumor drug radicicol

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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