View source for 9m3u


==Crystal structure of human pyruvate dehydrogenase kinase isoform 2 in complex with ATP competitive inhibitor 24==
<StructureSection load='9m3u' size='340' side='right'caption='[[9m3u]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[9m3u]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9M3U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9M3U FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.92&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1EQJ:2-cyano-~{N}-[(3~{R})-1-[(3~{S})-3-ethyl-7-(ethylamino)-5-fluoranyl-2-oxidanylidene-1~{H}-indol-3-yl]piperidin-3-yl]-2-azaspiro[3.3]heptane-6-carboxamide'>A1EQJ</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=TF3:N-(2-AMINOETHYL)-2-{3-CHLORO-4-[(4-ISOPROPYLBENZYL)OXY]PHENYL}+ACETAMIDE'>TF3</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9m3u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9m3u OCA], [https://pdbe.org/9m3u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9m3u RCSB], [https://www.ebi.ac.uk/pdbsum/9m3u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9m3u ProSAT]</span></td></tr>
</table>
== Function ==
[https://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 ==
Multiple screening approaches were carried out to identify novel chemistry starting for Pyruvate Dehydrogenase Kinases (PDHKs) inhibitors. Through hit triaging efforts and structure-based optimization, two series of ATP competitive inhibitors with single digit nanomolar enzymatic potency for PDHK1/2 and around 10-100-fold selectivity over PDHK4/3 were discovered. Approach of covalent inhibitor was explored to successfully improve the cellular target engagement to single digit micromolar range.

Discovery of ATP competitive PDHK1/2 dual inhibitors.,Xu H, Ding D, Han X, Miao K, Liang C, Yun H, Zhu W, Dey F, Zhao D, Wu Y, Reutlinger M, Yang J, Zhai G, Lin Z, Li C, Wu W, Xu B, Han L, Chen S, Huang X, Casagrande F, Hilbert M, Strebel Q, Wichert M, Westwood P, Schafer R, Roth D, Heer D, Tian X, Ma T, Zhang T, Zhao J, Urich E, Xia G, Lassen K, Shen HC, Zou G Bioorg Med Chem Lett. 2025 Mar 17;122:130190. doi: 10.1016/j.bmcl.2025.130190. PMID:40107630<ref>PMID:40107630</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 9m3u" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Chen S]]
[[Category: Han L]]
[[Category: Xu ZH]]