3crl

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3crl, resolution 2.61Å ()
Ligands: , ,
Non-Standard Residues:
Gene: Pdk2 (Rattus norvegicus), DLAT, DLTA (Homo sapiens)
Activity: [Pyruvate_dehydrogenase_(acetyl-transferring)_kinase [Pyruvate dehydrogenase (acetyl-transferring)] kinase], with EC number 2.7.11.2
Related: 3crk


Resources: FirstGlance, OCA, RCSB, PDBsum
Coordinates: save as pdb, mmCIF, xml


Contents

Crystal structure of the PDHK2-L2 complex.

Publication Abstract from PubMed

PDHK2 is a mitochondrial protein kinase that phosphorylates pyruvate dehydrogenase complex, thereby down-regulating the oxidation of pyruvate. Here, we present the crystal structure of PDHK2 bound to the inner lipoyl-bearing domain of dihydrolipoamide transacetylase (L2) determined with or without bound adenylyl imidodiphosphate. Both structures reveal a PDHK2 dimer complexed with two L2 domains. Comparison with apo-PDHK2 shows that L2 binding causes rearrangements in PDHK2 structure that affect the L2- and E1-binding sites. Significant differences are found between PDHK2 and PDHK3 with respect to the structure of their lipoyllysine-binding cavities, providing the first structural support to a number of studies showing that these isozymes are markedly different with respect to their affinity for the L2 domain. Both structures display a novel type II potassium-binding site located on the PDHK2 interface with the L2 domain. Binding of potassium ion at this site rigidifies the interface and appears to be critical in determining the strength of L2 binding. Evidence is also presented that potassium ions are indispensable for the cross-talk between the nucleotide- and L2-binding sites of PDHK2. The latter is believed to be essential for the movement of PDHK2 along the surface of the transacetylase scaffold.

Structural and functional insights into the molecular mechanisms responsible for the regulation of pyruvate dehydrogenase kinase 2., Green T, Grigorian A, Klyuyeva A, Tuganova A, Luo M, Popov KM, J Biol Chem. 2008 Jun 6;283(23):15789-98. Epub 2008 Apr 3. PMID:18387944

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

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

[PDK2_RAT] 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] [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

3crl is a 4 chain structure with sequence from Homo sapiens and Rattus norvegicus. Full crystallographic information is available from OCA.

See Also

Reference

  • Green T, Grigorian A, Klyuyeva A, Tuganova A, Luo M, Popov KM. Structural and functional insights into the molecular mechanisms responsible for the regulation of pyruvate dehydrogenase kinase 2. J Biol Chem. 2008 Jun 6;283(23):15789-98. Epub 2008 Apr 3. PMID:18387944 doi:10.1074/jbc.M800311200
  1. Popov KM, Kedishvili NY, Zhao Y, Gudi R, Harris RA. Molecular cloning of the p45 subunit of pyruvate dehydrogenase kinase. J Biol Chem. 1994 Nov 25;269(47):29720-4. PMID:7961963
  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. Mayers RM, Butlin RJ, Kilgour E, Leighton B, Martin D, Myatt J, Orme JP, Holloway BR. AZD7545, a novel inhibitor of pyruvate dehydrogenase kinase 2 (PDHK2), activates pyruvate dehydrogenase in vivo and improves blood glucose control in obese (fa/fa) Zucker rats. Biochem Soc Trans. 2003 Dec;31(Pt 6):1165-7. PMID:14641018 doi:10.1042/
  4. Boulatnikov I, Popov KM. Formation of functional heterodimers by isozymes 1 and 2 of pyruvate dehydrogenase kinase. Biochim Biophys Acta. 2003 Feb 21;1645(2):183-92. PMID:12573248
  5. Hurd TR, Collins Y, Abakumova I, Chouchani ET, Baranowski B, Fearnley IM, Prime TA, Murphy MP, James AM. Inactivation of pyruvate dehydrogenase kinase 2 by mitochondrial reactive oxygen species. J Biol Chem. 2012 Oct 12;287(42):35153-60. doi: 10.1074/jbc.M112.400002. Epub, 2012 Aug 21. PMID:22910903 doi:10.1074/jbc.M112.400002

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