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[[Image:2vo3.png|left|200px]]


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==Structure of PKA-PKB chimera complexed with C-(4-(4-Chlorophenyl)-1-(7H-pyrrolo(2,3-d)pyrimidin-4-yl)piperidin-4-yl)methylamine==
The line below this paragraph, containing "STRUCTURE_2vo3", creates the "Structure Box" on the page.
<StructureSection load='2vo3' size='340' side='right'caption='[[2vo3]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
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== Structural highlights ==
or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
<table><tr><td colspan='2'>[[2vo3]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VO3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2VO3 FirstGlance]. <br>
or leave the SCENE parameter empty for the default display.
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.98&#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=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=M04:1-[4-(4-CHLOROBENZYL)-1-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PIPERIDIN-4-YL]METHANAMINE'>M04</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
{{STRUCTURE_2vo3| PDB=2vo3 |  SCENE= }}
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2vo3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vo3 OCA], [https://pdbe.org/2vo3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2vo3 RCSB], [https://www.ebi.ac.uk/pdbsum/2vo3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2vo3 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/KAPCA_BOVIN KAPCA_BOVIN] Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, TRPC1 and VASP. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). TRPC1 activation by phosphorylation promotes Ca(2+) influx, essential for the increase in permeability induced by thrombin in confluent endothelial monolayers. PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Regulates negatively tight junction (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT) (By similarity).
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/vo/2vo3_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2vo3 ConSurf].
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<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Fragment-based screening identified 7-azaindole as a protein kinase B inhibitor scaffold. Fragment elaboration using iterative crystallography of inhibitor-PKA-PKB chimera complexes efficiently guided improvements in the potency and selectivity of the compounds, resulting in the identification of nanomolar 6-(piperidin-1-yl)purine, 4-(piperidin-1-yl)-7-azaindole, and 4-(piperidin-1-yl)pyrrolo[2,3- d]pyrimidine inhibitors of PKBbeta with antiproliferative activity and showing pathway inhibition in cells. A divergence in the binding mode was seen between 4-aminomethylpiperidine and 4-aminopiperidine containing molecules. Selectivity for PKB vs PKA was observed with 4-aminopiperidine derivatives, and the most PKB-selective inhibitor (30-fold) showed significantly different bound conformations between PKA and PKA-PKB chimera.


===STRUCTURE OF PKA-PKB CHIMERA COMPLEXED WITH C-(4-(4-CHLOROPHENYL)-1-(7H-PYRROLO(2,3-D)PYRIMIDIN-4-YL)PIPERIDIN-4-YL)METHYLAMINE===
Identification of 4-(4-Aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as Selective Inhibitors of Protein Kinase B through Fragment Elaboration.,Caldwell JJ, Davies TG, Donald A, McHardy T, Rowlands MG, Aherne GW, Hunter LK, Taylor K, Ruddle R, Raynaud FI, Verdonk M, Workman P, Garrett MD, Collins I J Med Chem. 2008 Apr 10;51(7):2147-57. Epub 2008 Mar 18. PMID:18345609<ref>PMID:18345609</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 2vo3" style="background-color:#fffaf0;"></div>


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==See Also==
The line below this paragraph, {{ABSTRACT_PUBMED_18345609}}, adds the Publication Abstract to the page
*[[CAMP-dependent protein kinase 3D structures|CAMP-dependent protein kinase 3D structures]]
(as it appears on PubMed at http://www.pubmed.gov), where 18345609 is the PubMed ID number.
== References ==
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<references/>
{{ABSTRACT_PUBMED_18345609}}
__TOC__
 
</StructureSection>
==About this Structure==
2VO3 is a 2 chains structure of sequences from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VO3 OCA].
 
==Reference==
<ref group="xtra">PMID:18345609</ref><references group="xtra"/>
[[Category: Bos taurus]]
[[Category: Bos taurus]]
[[Category: CAMP-dependent protein kinase]]
[[Category: Homo sapiens]]
[[Category: Aherne, G W.]]
[[Category: Large Structures]]
[[Category: Caldwell, J J.]]
[[Category: Aherne GW]]
[[Category: Collins, I.]]
[[Category: Caldwell JJ]]
[[Category: Davies, T G.]]
[[Category: Collins I]]
[[Category: Donald, A.]]
[[Category: Davies TG]]
[[Category: Garrett, M D.]]
[[Category: Donald A]]
[[Category: Hunter, L K.]]
[[Category: Garrett MD]]
[[Category: Mchardy, T.]]
[[Category: Hunter LK]]
[[Category: Raynaud, F I.]]
[[Category: McHardy T]]
[[Category: Rowlands, M G.]]
[[Category: Raynaud FI]]
[[Category: Ruddle, R.]]
[[Category: Rowlands MG]]
[[Category: Taylor, K.]]
[[Category: Ruddle R]]
[[Category: Verdonk, M.]]
[[Category: Taylor K]]
[[Category: Workman, P.]]
[[Category: Verdonk M]]
[[Category: Atp-binding]]
[[Category: Workman P]]
[[Category: Camp]]
[[Category: Cytoplasm]]
[[Category: Kinase]]
[[Category: Lipoprotein]]
[[Category: Myristate]]
[[Category: Nucleotide-binding]]
[[Category: Nucleus]]
[[Category: Phosphoprotein]]
[[Category: Protein kinase inhibitor]]
[[Category: Serine/threonine-protein kinase]]
[[Category: Transferase]]
 
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