5m4e: Difference between revisions
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==Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase== | ==Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase== | ||
<StructureSection load='5m4e' size='340' side='right' caption='[[5m4e]], [[Resolution|resolution]] 1.90Å' scene=''> | <StructureSection load='5m4e' size='340' side='right'caption='[[5m4e]], [[Resolution|resolution]] 1.90Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5m4e]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5M4E OCA]. For a <b>guided tour on the structure components</b> use [http:// | <table><tr><td colspan='2'>[[5m4e]] 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=5M4E OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5M4E FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7F9:~{N}-[2-(ETHYLAMINO)-2-OXIDANYLIDENE-ETHYL]-~{N}-(4-METHOXYPHENYL)-2,4-BIS(OXIDANYL)BENZAMIDE'>7F9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7F9:~{N}-[2-(ETHYLAMINO)-2-OXIDANYLIDENE-ETHYL]-~{N}-(4-METHOXYPHENYL)-2,4-BIS(OXIDANYL)BENZAMIDE'>7F9</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http:// | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">HSP90AA1, HSP90A, HSPC1, HSPCA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=5m4e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5m4e OCA], [http://pdbe.org/5m4e PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5m4e RCSB], [http://www.ebi.ac.uk/pdbsum/5m4e PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5m4e ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
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</div> | </div> | ||
<div class="pdbe-citations 5m4e" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5m4e" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Heat Shock Protein structures|Heat Shock Protein structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Baker, L M]] | [[Category: Baker, L M]] | ||
[[Category: Cancer]] | [[Category: Cancer]] | ||
Revision as of 14:00, 12 August 2020
Application of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase KinaseApplication of Off-Rate Screening in the Identification of Novel Pan-Isoform Inhibitors of Pyruvate Dehydrogenase Kinase
Structural highlights
Function[HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.[1] [2] Publication Abstract from PubMedLibraries 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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