9m3o

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m (Protected "9m3o" [edit=sysop:move=sysop])
Current revision (09:29, 2 April 2025) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 9m3o is ON HOLD
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==Crystal structure of human pyruvate dehydrogenase kinase isoform 1 in complex with ATP competitive inhibitor 8==
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<StructureSection load='9m3o' size='340' side='right'caption='[[9m3o]], [[Resolution|resolution]] 1.76&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[9m3o]] 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=9M3O OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9M3O FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.762&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1EMR:6-fluoranyl-8-(methylamino)-~{N}-(pyrimidin-5-ylmethyl)-9~{H}-pyrido[2,3-b]indole-3-carboxamide'>A1EMR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=K:POTASSIUM+ION'>K</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9m3o FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9m3o OCA], [https://pdbe.org/9m3o PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9m3o RCSB], [https://www.ebi.ac.uk/pdbsum/9m3o PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9m3o ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/PDK1_HUMAN PDK1_HUMAN] Serine/threonine kinase that plays a key role in 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. Plays an important role in cellular responses to hypoxia and is important for cell proliferation under hypoxia. Protects cells against apoptosis in response to hypoxia and oxidative stress.<ref>PMID:7499431</ref> <ref>PMID:18541534</ref> <ref>PMID:22195962</ref> <ref>PMID:17683942</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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Authors: Xu, Z.H., Chen, S.
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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>
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Description: Crystal structure of human pyruvate dehydrogenase kinase isoform 1 in complex with ATP competitive inhibitor 8
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Xu, Z.H]]
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<div class="pdbe-citations 9m3o" style="background-color:#fffaf0;"></div>
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[[Category: Chen, S]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Chen S]]
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[[Category: Xu ZH]]

Current revision

Crystal structure of human pyruvate dehydrogenase kinase isoform 1 in complex with ATP competitive inhibitor 8

PDB ID 9m3o

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