View source for 4a06


==Human PDK1 Kinase Domain in Complex with Allosteric Activator PS114 Bound to the PIF-Pocket==
<StructureSection load='4a06' size='340' side='right'caption='[[4a06]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4a06]] 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=4A06 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4A06 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]] 2&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A06:(3S)-4-(5-CHLORO-1H-BENZIMIDAZOL-2-YL)-3-(4-CHLOROPHENYL)BUTANOIC+ACID'>A06</scene>, <scene name='pdbligand=ATP:ADENOSINE-5-TRIPHOSPHATE'>ATP</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</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=4a06 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4a06 OCA], [https://pdbe.org/4a06 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4a06 RCSB], [https://www.ebi.ac.uk/pdbsum/4a06 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4a06 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> 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Protein kinases are key mediators of cellular signaling, and therefore, their activities are tightly controlled. AGC kinases are regulated by phosphorylation and by N- and C-terminal regions. Here, we studied the molecular mechanism of inhibition of atypical PKCzeta and found that the inhibition by the N-terminal region cannot be explained by a simple pseudosubstrate inhibitory mechanism. Notably, we found that the C1 domain allosterically inhibits PKCzeta activity and verified an allosteric communication between the PIF-pocket of atypical PKCs and the binding site of the C1 domain. Finally, we developed low-molecular-weight compounds that bind to the PIF-pocket and allosterically inhibit PKCzeta activity. This work establishes a central role for the PIF-pocket on the regulation of PKCzeta and allows us to envisage development of drugs targeting the PIF-pocket that can either activate or inhibit AGC kinases.

Allosteric Regulation of Protein Kinase PKCzeta by the N-Terminal C1 Domain and Small Compounds to the PIF-Pocket.,Lopez-Garcia LA, Schulze JO, Frohner W, Zhang H, Suss E, Weber N, Navratil J, Amon S, Hindie V, Zeuzem S, Jorgensen TJ, Alzari PM, Neimanis S, Engel M, Biondi RM Chem Biol. 2011 Nov 23;18(11):1463-1473. PMID:22118680<ref>PMID:22118680</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4a06" style="background-color:#fffaf0;"></div>

==See Also==
*[[Pdk1 3D structures|Pdk1 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Alzari PM]]
[[Category: Biondi RM]]
[[Category: Engel M]]
[[Category: Froehner W]]
[[Category: Hindie V]]
[[Category: Lopez-Garcia LA]]
[[Category: Navratil J]]
[[Category: Neimanis S]]
[[Category: Schulze JO]]
[[Category: Zeuzem S]]
[[Category: Zhang H]]