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5m4p

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Revision as of 06:27, 24 October 2018

Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase

Structural highlights

5m4p 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:	, ,
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

Libraries of nonpurified resorcinol amide derivatives were screened by surface plasmon resonance (SPR) to determine the binding dissociation constant (off-rate, kd) for compounds binding to the pyruvate dehydrogenase kinase (PDHK) enzyme. Parallel off-rate measurements against HSP90 and application of structure-based drug design enabled rapid hit to lead progression in a program to identify pan-isoform ATP-competitive inhibitors of PDHK. Lead optimization identified selective sub-100-nM inhibitors of the enzyme which significantly reduced phosphorylation of the E1alpha subunit in the PC3 cancer cell line in vitro.

Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase.,Brough PA, Baker L, Bedford S, Brown K, Chavda S, Chell V, D'Alessandro J, Davies NG, Davis B, Le Strat L, Macias AT, Maddox D, Mahon PC, Massey AJ, Matassova N, McKenna S, Moore JD, Murray JB, Northfield CJ, Parry C, Parsons R, Roughley SD, Shaw T, Simmonite H, Stokes S, Surgenor A, Stefaniak E, Robertson A, Wang Y, Webb P, Whitehead N, Wood M J Med Chem. 2017 Feb 15. doi: 10.1021/acs.jmedchem.6b01478. PMID:28199108^[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
↑ Brough PA, Baker L, Bedford S, Brown K, Chavda S, Chell V, D'Alessandro J, Davies NG, Davis B, Le Strat L, Macias AT, Maddox D, Mahon PC, Massey AJ, Matassova N, McKenna S, Moore JD, Murray JB, Northfield CJ, Parry C, Parsons R, Roughley SD, Shaw T, Simmonite H, Stokes S, Surgenor A, Stefaniak E, Robertson A, Wang Y, Webb P, Whitehead N, Wood M. Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase. J Med Chem. 2017 Feb 15. doi: 10.1021/acs.jmedchem.6b01478. PMID:28199108 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01478

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/5m4p"

@@ Line 3: / Line 3: @@
 <StructureSection load='5m4p' size='340' side='right' caption='[[5m4p]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5m4p]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M4P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M4P FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5m4p]] 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=5M4P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M4P FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7FE:~{N}-[4-(2-CHLORANYL-5-METHYL-PYRIMIDIN-4-YL)PHENYL]-2,4-BIS(OXIDANYL)-~{N}-[[4-(PYRROLIDIN-1-YLMETHYL)PHENYL]METHYL]BENZAMIDE'>7FE</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=TF3:N-(2-AMINOETHYL)-2-{3-CHLORO-4-[(4-ISOPROPYLBENZYL)OXY]PHENYL}+ACETAMIDE'>TF3</scene></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=5m4p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m4p OCA], [http://pdbe.org/5m4p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m4p RCSB], [http://www.ebi.ac.uk/pdbsum/5m4p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m4p ProSAT]</span></td></tr>
@@ Line 19: / Line 20: @@
 </div>
 <div class="pdbe-citations 5m4p" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Pyruvate dehydrogenase kinase|Pyruvate dehydrogenase kinase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Baker, L M]]
 [[Category: Brough, P]]

5m4p

From Proteopedia

Revision as of 06:27, 24 October 2018

Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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