View source for 5ack


==Human PDK1 Kinase Domain in Complex with Allosteric Compound 7 Bound to the PIF-Pocket==
<StructureSection load='5ack' size='340' side='right'caption='[[5ack]], [[Resolution|resolution]] 1.24&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[5ack]] 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=5ACK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ACK FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=DTD:DITHIANE+DIOL'>DTD</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=SVQ:1-(4-CHLOROPHENETHYL)-2-(2-CHLOROPHENYL)-6-OXOPIPERIDINE-3-CARBOXYLIC+ACID'>SVQ</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=5ack FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ack OCA], [https://pdbe.org/5ack PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5ack RCSB], [https://www.ebi.ac.uk/pdbsum/5ack PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5ack ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/PDPK1_HUMAN PDPK1_HUMAN] Serine/threonine kinase which acts as a master kinase, phosphorylating and activating a subgroup of the AGC family of protein kinases. Its targets include: protein kinase B (PKB/AKT1, PKB/AKT2, PKB/AKT3), p70 ribosomal protein S6 kinase (RPS6KB1), p90 ribosomal protein S6 kinase (RPS6KA1, RPS6KA2 and RPS6KA3), cyclic AMP-dependent protein kinase (PRKACA), protein kinase C (PRKCD and PRKCZ), serum and glucocorticoid-inducible kinase (SGK1, SGK2 and SGK3), p21-activated kinase-1 (PAK1), protein kinase PKN (PKN1 and PKN2). Plays a central role in the transduction of signals from insulin by providing the activating phosphorylation to PKB/AKT1, thus propagating the signal to downstream targets controlling cell proliferation and survival, as well as glucose and amino acid uptake and storage. Negatively regulates the TGF-beta-induced signaling by: modulating the association of SMAD3 and SMAD7 with TGF-beta receptor, phosphorylating SMAD2, SMAD3, SMAD4 and SMAD7, preventing the nuclear translocation of SMAD3 and SMAD4 and the translocation of SMAD7 from the nucleus to the cytoplasm in response to TGF-beta. Activates PPARG transcriptional activity and promotes adipocyte differentiation. Activates the NF-kappa-B pathway via phosphorylation of IKKB. The tyrosine phosphorylated form is crucial for the regulation of focal adhesions by angiotensin II. Controls proliferation, survival, and growth of developing pancreatic cells. Participates in the regulation of Ca(2+) entry and Ca(2+)-activated K(+) channels of mast cells. Essential for the motility of vascular endothelial cells (ECs) and is involved in the regulation of their chemotaxis. Plays a critical role in cardiac homeostasis by serving as a dual effector for cell survival and beta-adrenergic response. Plays an important role during thymocyte development by regulating the expression of key nutrient receptors on the surface of pre-T cells and mediating Notch-induced cell growth and proliferative responses. Provides negative feedback inhibition to toll-like receptor-mediated NF-kappa-B activation in macrophages. Isoform 3 is catalytically inactive.<ref>PMID:9094314</ref> <ref>PMID:9768361</ref> <ref>PMID:9707564</ref> <ref>PMID:9445476</ref> <ref>PMID:10480933</ref> <ref>PMID:10995762</ref> <ref>PMID:12167717</ref> <ref>PMID:14585963</ref> <ref>PMID:14604990</ref> <ref>PMID:10226025</ref> <ref>PMID:16207722</ref> <ref>PMID:16251192</ref> <ref>PMID:17327236</ref> <ref>PMID:17371830</ref> <ref>PMID:18835241</ref> 
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== Publication Abstract from PubMed ==
The rational design of allosteric kinase modulators is challenging but rewarding. The protein kinase PDK1, which lies at the center of the growth-factor signaling pathway, possesses an allosteric regulatory site previously validated both in vitro and in cells. ANCHOR.QUERY software was used to discover a potent allosteric PDK1 kinase modulator. Using a recently published PDK1 compound as a template, several new scaffolds that bind to the allosteric target site were generated and one example was validated. The inhibitor can be synthesized in one step by multicomponent reaction (MCR) chemistry when using the ANCHOR.QUERY approach. Our results are significant because the outlined approach allows rapid and efficient scaffold hopping from known molecules into new easily accessible and biologically active ones. Based on increasing interest in allosteric-site drug discovery, we foresee many potential applications for this approach.

Discovery of a Potent Allosteric Kinase Modulator by Combining Computational and Synthetic Methods.,Kroon E, Schulze JO, Suss E, Camacho CJ, Biondi RM, Domling A Angew Chem Int Ed Engl. 2015 Sep 4. doi: 10.1002/anie.201506310. PMID:26385475<ref>PMID:26385475</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 5ack" style="background-color:#fffaf0;"></div>

==See Also==
*[[Pdk1 3D structures|Pdk1 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Biondi RM]]
[[Category: Doemling A]]
[[Category: Kroon E]]
[[Category: Schulze JO]]