View source for 7ebh


==Crystal structure of human pyruvate dehydrogenase kinase 2 in complex with compound 13==
<StructureSection load='7ebh' size='340' side='right'caption='[[7ebh]], [[Resolution|resolution]] 1.96&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7ebh]] 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=7EBH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7EBH 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]] 1.96&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=J0F:5-bromanyl-2-methyl-6-propyl-7H-pyrrolo[2,3-d]pyrimidine'>J0F</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=7ebh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ebh OCA], [https://pdbe.org/7ebh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ebh RCSB], [https://www.ebi.ac.uk/pdbsum/7ebh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ebh 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 ==
A fragment-based lead discovery approach was applied to Pyruvate Dehydrogenase Kinases (PDHKs) to discover inhibitors against the ATP binding site with novel chemotypes. X-ray fragment screening toward PDHK4 provided a fragment hit 1 with a characteristic interaction in a deep pocket of the ATP binding site. While known inhibitors utilize several water molecules in a deep pocket to form water-mediated hydrogen bond interactions, the fragment hit binds deeper in the pocket with a hydrophobic group. Displacement of a remaining water molecule in the pocket led to the identification of lead compound 7 with a notable improvement in inhibition potency. This lead compound possessed high ligand efficiency (LE) and showed decent selectivity profile. Two additional lead compounds 10 and 13 with new scaffolds with tricyclic and bicyclic cores were generated by merging structural information of another fragment hit 2. The characteristic interaction of these novel inhibitors in a deep pocket provides new structural insights about PDHKs ATP binding site and opens a novel direction for the development of PDHKs inhibitors.

Fragment-based lead discovery to identify novel inhibitors that target the ATP binding site of pyruvate dehydrogenase kinases.,Akaki T, Bessho Y, Ito T, Fujioka S, Ubukata M, Mori G, Yamanaka K, Orita T, Doi S, Iwanaga T, Ikegashira K, Hantani Y, Nakanishi I, Adachi T Bioorg Med Chem. 2021 Jul 8;44:116283. doi: 10.1016/j.bmc.2021.116283. PMID:34274549<ref>PMID:34274549</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7ebh" style="background-color:#fffaf0;"></div>

==See Also==
*[[Pyruvate dehydrogenase kinase|Pyruvate dehydrogenase kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Adachi T]]
[[Category: Doi S]]
[[Category: Iwanaga T]]
[[Category: Orita T]]