View source for 6lil


==Crystal structure of human PDK2 complexed with an allosteric inhibitor compound 8c==
<StructureSection load='6lil' size='340' side='right'caption='[[6lil]], [[Resolution|resolution]] 1.93&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6lil]] is a 2 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=6LIL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6LIL 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]] 1.93&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EGX:1-(1-piperidin-4-ylpyrazol-4-yl)anthracene-9,10-dione'>EGX</scene>, <scene name='pdbligand=FLC:CITRATE+ANION'>FLC</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</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'>[https://proteopedia.org/fgij/fg.htm?mol=6lil FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6lil OCA], [https://pdbe.org/6lil PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6lil RCSB], [https://www.ebi.ac.uk/pdbsum/6lil PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6lil 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 ==
Pyruvate dehydrogenase kinase (PDK) controls the activity of pyruvate decarboxylase complex (PDC) by phosphorylating key serine residues on the E1 subunit, which leads to a decreased oxidative phosphorylation in mitochondria. Inhibition of PDK activity by natural/synthetic compounds has been shown to reverse the Warburg effect, a characteristic metabolism in cancer cells. PDK-PDC axis also has been associated with diabetes and heart disease. Therefore, regulation of PDK activity has been considered as a promising strategy to treat related diseases. Here we present the X-ray crystal structure of PDK2 complexed with a recently identified PDK4 inhibitor, compound 8c, which has been predicted to bind at the lipoyl-binding site and interrupt intermolecular interactions with the E2-E3bp subunits of PDC. The co-crystal structure confirmed the specific binding location of compound 8c and revealed the remote conformational change in the ATP-binding pocket. In addition, two novel 4,5-diarylisoxazole derivatives, GM10030 and GM67520, were synthesized and used for structural studies, which target the ATP-binding site of PDK2. These compounds bind to PDK2 with a sub-100nM affinity as determined by isothermal titration calorimetry experiments. Notably, the crystal structure of the PDK2-GM10030 complex displays unprecedented asymmetric conformation of human PDK2 dimer, especially in the ATP-lids and C-terminal tails.

Structural basis for the inhibition of PDK2 by novel ATP- and lipoyl-binding site targeting compounds.,Kang J, Pagire HS, Kang D, Song YH, Lee IK, Lee KT, Park CJ, Ahn JH, Kim J Biochem Biophys Res Commun. 2020 Jun 30;527(3):778-784. doi:, 10.1016/j.bbrc.2020.04.102. Epub 2020 May 20. PMID:32444142<ref>PMID:32444142</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6lil" style="background-color:#fffaf0;"></div>

==See Also==
*[[Pyruvate dehydrogenase kinase|Pyruvate dehydrogenase kinase]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Kang J]]
[[Category: Kim J]]