2pnr

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Template:STRUCTURE 2pnr

Contents

Crystal Structure of the asymmetric Pdk3-l2 Complex

Template:ABSTRACT PUBMED 17532006

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.

About this Structure

2pnr is a 6 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA.

See Also

Reference

  • Devedjiev Y, Steussy CN, Vassylyev DG. Crystal structure of an asymmetric complex of pyruvate dehydrogenase kinase 3 with lipoyl domain 2 and its biological implications. J Mol Biol. 2007 Jul 13;370(3):407-16. Epub 2007 May 10. PMID:17532006 doi:10.1016/j.jmb.2007.04.083
  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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

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