5j6a

From Proteopedia

(Difference between revisions)

Revision as of 17:50, 15 November 2017

Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PS46

Structural highlights

5j6a is a 1 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:	4mp2, 4mp7, 4mpc, 4mpe, 4mpn, 5j71
Gene:	PDK2, PDHK2 (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

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 kinases 1-4 (PDK1-4) negatively control activity of the pyruvate dehydrogenase complex (PDC) and are up-regulated in obesity, diabetes, heart failure and cancer. We reported earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)sulfonyl)benzene-1,3-diol] (1) and PS10 [2-((2,4-dihydroxyphenyl)sulfonyl)isoindoline-4,6-diol] (2) that targeted the ATP-binding pocket in PDKs. Here, we developed a new generation of PDK inhibitors by extending the dihydroxyphenyl sulfonylisoindoline scaffold in 1 and 2 to the entrance region of the ATP-binding pocket in PDK2. The lead inhibitor PS46 [(S)-3-amino-4-(4-((2-((2,4-dihydroxyphenyl)sulfonyl)isoindolin-5-yl)amino)piperi din-1-yl)-4-oxobutanamide] (17) shows a ~8-fold lower IC50 (58 nM) than 2 (456 nM). In the crystal structure, the asparagine moiety in 17 provides additional interactions with Glu-262 from PDK2. Treatment of diet-induced obese mice with 17 resulted in significant liver-specific augmentation of PDC activity, accompanied by improved glucose tolerance and drastically reduced hepatic steatosis. These findings support 17 as a potential glucose-lowering therapeutic targeting liver for obesity and type 2 diabetes.

Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-targeting Pyruvate Dehydrogenase Kinase Inhibitors.,Tso SC, Lou M, Wu CY, Gui WJ, Chuang JL, Morlock LK, Williams NS, Wynn RM, Qi X, Chuang DT J Med Chem. 2017 Jan 13. doi: 10.1021/acs.jmedchem.6b01540. PMID:28085286^[7]

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

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, Lou M, Wu CY, Gui WJ, Chuang JL, Morlock LK, Williams NS, Wynn RM, Qi X, Chuang DT. Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-targeting Pyruvate Dehydrogenase Kinase Inhibitors. J Med Chem. 2017 Jan 13. doi: 10.1021/acs.jmedchem.6b01540. PMID:28085286 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01540

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5j6a"

@@ Line 3: / Line 3: @@
 <StructureSection load='5j6a' size='340' side='right' caption='[[5j6a]], [[Resolution|resolution]] 2.04&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5j6a]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5J6A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J6A FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5j6a]] 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=5J6A OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5J6A FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=P46:(3S)-3-AMINO-4-[4-({2-[(2,4-DIHYDROXYPHENYL)SULFONYL]-2H-ISOINDOL-5-YL}AMINO)PIPERIDIN-1-YL]-4-OXOBUTANAMIDE'>P46</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4mp2|4mp2]], [[4mp7|4mp7]], [[4mpc|4mpc]], [[4mpe|4mpe]], [[4mpn|4mpn]], [[5j71|5j71]]</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=5j6a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5j6a OCA], [http://pdbe.org/5j6a PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5j6a RCSB], [http://www.ebi.ac.uk/pdbsum/5j6a PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5j6a ProSAT]</span></td></tr>
@@ Line 20: / Line 21: @@
 </div>
 <div class="pdbe-citations 5j6a" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Pyruvate dehydrogenase kinase|Pyruvate dehydrogenase kinase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Chuang, D T]]
 [[Category: Chuang, J L]]

5j6a

From Proteopedia

Revision as of 17:50, 15 November 2017

Crystal structure of pyruvate dehydrogenase kinase isoform 2 in complex with inhibitor PS46

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

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