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2zdy

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Revision as of 07:36, 31 July 2019

Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4

Structural highlights

2zdy 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:	2zdx
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

Function

[PDK4_HUMAN] Serine/threonine kinase that plays a key role in 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 in response to prolonged fasting and starvation. Plays an important role in maintaining normal blood glucose levels under starvation, and is involved in the insulin signaling cascade. 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. In the fed state, mediates cellular responses to glucose levels and to a high-fat diet. Regulates both fatty acid oxidation and de novo fatty acid biosynthesis. Plays a role in the generation of reactive oxygen species. Protects detached epithelial cells against anoikis. Plays a role in cell proliferation via its role in regulating carbohydrate and fatty acid metabolism.^[1] ^[2] ^[3] ^[4]

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

The mitochondrial pyruvate dehydrogenase complex (PDC) catalyzes the oxidative decarboxylation of pyruvate to acetyl-CoA. PDC activity is tightly regulated by four members of a family of pyruvate dehydrogenase kinase isoforms (PDK1-4), which phosphorylate and inactivate PDC. Recently, the development of specific inhibitors of PDK4 has become an especially important focus for the pharmaceutical management of diabetes and obesity. In this study, crystal structures of human PDK4 complexed with either AMPPNP, ADP or the inhibitor M77976 were determined. ADP-bound PDK4 has a slightly wider active-site cleft and a more disordered ATP lid compared with AMPPNP-bound PDK4, although both forms of PDK4 assume open conformations with a wider active-site cleft than that in the closed conformation of the previously reported ADP-bound PDK2 structure. M77976 binds to the ATP-binding pocket of PDK4 and causes local conformational changes with complete disordering of the ATP lid. M77976 binding also leads to a large domain rearrangement that further expands the active-site cleft of PDK4 compared with the ADP- and AMPPNP-bound forms. Biochemical analyses revealed that M77976 inhibits PDK4 with increased potency compared with the previously characterized PDK inhibitor radicicol. Thus, the present structures demonstrate for the first time the flexible and dynamic aspects of PDK4 in the open conformation and provide a basis for the development of novel inhibitors targeting the nucleotide-binding pocket of PDK4.

Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4.,Kukimoto-Niino M, Tokmakov A, Terada T, Ohbayashi N, Fujimoto T, Gomi S, Shiromizu I, Kawamoto M, Matsusue T, Shirouzu M, Yokoyama S Acta Crystallogr D Biol Crystallogr. 2011 Sep;67(Pt 9):763-73. doi:, 10.1107/S090744491102405X. Epub 2011 Aug 9. PMID:21904029^[5]

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

References

↑ Abbot EL, McCormack JG, Reynet C, Hassall DG, Buchan KW, Yeaman SJ. Diverging regulation of pyruvate dehydrogenase kinase isoform gene expression in cultured human muscle cells. FEBS J. 2005 Jun;272(12):3004-14. PMID:15955060 doi:http://dx.doi.org/10.1111/j.1742-4658.2005.04713.x
↑ Grassian AR, Metallo CM, Coloff JL, Stephanopoulos G, Brugge JS. Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation. Genes Dev. 2011 Aug 15;25(16):1716-33. doi: 10.1101/gad.16771811. PMID:21852536 doi:http://dx.doi.org/10.1101/gad.16771811
↑ Kulkarni SS, Salehzadeh F, Fritz T, Zierath JR, Krook A, Osler ME. Mitochondrial regulators of fatty acid metabolism reflect metabolic dysfunction in type 2 diabetes mellitus. Metabolism. 2012 Feb;61(2):175-85. doi: 10.1016/j.metabol.2011.06.014. Epub 2011 , Aug 3. PMID:21816445 doi:http://dx.doi.org/10.1016/j.metabol.2011.06.014
↑ Wynn RM, Kato M, Chuang JL, Tso SC, Li J, Chuang DT. Pyruvate dehydrogenase kinase-4 structures reveal a metastable open conformation fostering robust core-free basal activity. J Biol Chem. 2008 Sep 12;283(37):25305-15. Epub 2008 Jul 24. PMID:18658136 doi:10.1074/jbc.M802249200
↑ Kukimoto-Niino M, Tokmakov A, Terada T, Ohbayashi N, Fujimoto T, Gomi S, Shiromizu I, Kawamoto M, Matsusue T, Shirouzu M, Yokoyama S. Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4. Acta Crystallogr D Biol Crystallogr. 2011 Sep;67(Pt 9):763-73. doi:, 10.1107/S090744491102405X. Epub 2011 Aug 9. PMID:21904029 doi:10.1107/S090744491102405X

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

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

@@ Line 1: / Line 1: @@
 ==Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4==
-<StructureSection load='2zdy' size='340' side='right' caption='[[2zdy]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
+<StructureSection load='2zdy' size='340' side='right'caption='[[2zdy]], [[Resolution|resolution]] 2.40&Aring;' scene=''>
 == Structural highlights ==
 <table><tr><td colspan='2'>[[2zdy]] is a 2 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=2ZDY OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2ZDY FirstGlance]. <br>
@@ Line 15: / Line 15: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/zd/2zdy_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/zd/2zdy_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 38: / Line 38: @@
 </StructureSection>
 [[Category: Human]]
+[[Category: Large Structures]]
 [[Category: Kawamoto, M]]
 [[Category: Kukimoto-Niino, M]]

2zdy

From Proteopedia

Revision as of 07:36, 31 July 2019

Inhibitor-bound structures of human pyruvate dehydrogenase kinase 4

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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