5m4m
From Proteopedia
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| - | '''Unreleased structure''' | ||
| - | + | ==Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase== | |
| + | <StructureSection load='5m4m' size='340' side='right' caption='[[5m4m]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[5m4m]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M4M OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5M4M FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7FW:~{N}-[4-[METHYL(QUINOXALIN-6-YLMETHYL)CARBAMOYL]PHENYL]-2,4-BIS(OXIDANYL)-~{N}-(PHENYLMETHYL)BENZAMIDE'>7FW</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='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=5m4m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m4m OCA], [http://pdbe.org/5m4m PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m4m RCSB], [http://www.ebi.ac.uk/pdbsum/5m4m PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m4m ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/PDK2_HUMAN 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.<ref>PMID:7499431</ref> <ref>PMID:9787110</ref> <ref>PMID:17222789</ref> <ref>PMID:19833728</ref> <ref>PMID:21283817</ref> <ref>PMID:22123926</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == 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<ref>PMID:28199108</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | + | <div class="pdbe-citations 5m4m" style="background-color:#fffaf0;"></div> | |
| - | [[Category: Baker, L | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Baker, L M]] | ||
[[Category: Brough, P]] | [[Category: Brough, P]] | ||
| + | [[Category: Surgenor, A]] | ||
| + | [[Category: Cancer]] | ||
| + | [[Category: Fragment screening]] | ||
| + | [[Category: Hsp90]] | ||
| + | [[Category: Kinase inhibitor]] | ||
| + | [[Category: Off-rate screening]] | ||
| + | [[Category: Pdhk]] | ||
| + | [[Category: Pdk1]] | ||
| + | [[Category: Pdk2]] | ||
| + | [[Category: Pdk3]] | ||
| + | [[Category: Pdk4]] | ||
| + | [[Category: Spr]] | ||
| + | [[Category: Transferase]] | ||
Revision as of 01:38, 11 March 2017
Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase
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Categories: Baker, L M | Brough, P | Surgenor, A | Cancer | Fragment screening | Hsp90 | Kinase inhibitor | Off-rate screening | Pdhk | Pdk1 | Pdk2 | Pdk3 | Pdk4 | Spr | Transferase
