View source for 2vo7


==Structure of PKA complexed with 4-(4-Chlorobenzyl)-1-(7H-pyrrolo(2,3- d)pyrimidin-4-yl)piperidin-4-ylamine==
<StructureSection load='2vo7' size='340' side='right'caption='[[2vo7]], [[Resolution|resolution]] 1.98&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2vo7]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bovin Bovin]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VO7 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=2VO7 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=M05:4-(4-CHLOROBENZYL)-1-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PIPERIDIN-4-AMINIUM'>M05</scene></td></tr>
<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1xh6|1xh6]], [[1xh9|1xh9]], [[2vnw|2vnw]], [[1ydr|1ydr]], [[1sve|1sve]], [[2uvz|2uvz]], [[1xh4|1xh4]], [[2uvx|2uvx]], [[1q8u|1q8u]], [[2f7e|2f7e]], [[2vo6|2vo6]], [[1kmu|1kmu]], [[1cmk|1cmk]], [[2uw7|2uw7]], [[2jds|2jds]], [[1q62|1q62]], [[2uw8|2uw8]], [[2gnf|2gnf]], [[2uzu|2uzu]], [[2uw3|2uw3]], [[2c1a|2c1a]], [[1smh|1smh]], [[2uw4|2uw4]], [[1veb|1veb]], [[2c1b|2c1b]], [[2gnl|2gnl]], [[1jlu|1jlu]], [[1xh7|1xh7]], [[2uzv|2uzv]], [[1q24|1q24]], [[2vny|2vny]], [[2uw6|2uw6]], [[1svg|1svg]], [[1kmw|1kmw]], [[1xha|1xha]], [[2gnj|2gnj]], [[2uvy|2uvy]], [[2vo0|2vo0]], [[2gnh|2gnh]], [[2gfc|2gfc]], [[1szm|1szm]], [[1q61|1q61]], [[2gng|2gng]], [[1ydt|1ydt]], [[2uzt|2uzt]], [[1q8w|1q8w]], [[1svh|1svh]], [[2uzw|2uzw]], [[2uw0|2uw0]], [[2jdv|2jdv]], [[2vo3|2vo3]], [[2uw5|2uw5]], [[2gni|2gni]], [[1xh5|1xh5]], [[1yds|1yds]], [[1stc|1stc]], [[2jdt|2jdt]], [[1q8t|1q8t]], [[1xh8|1xh8]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/cAMP-dependent_protein_kinase cAMP-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.11 2.7.11.11] </span></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=2vo7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vo7 OCA], [http://pdbe.org/2vo7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=2vo7 RCSB], [http://www.ebi.ac.uk/pdbsum/2vo7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=2vo7 ProSAT]</span></td></tr>
</table>
== Function ==
[[http://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). [[http://www.uniprot.org/uniprot/IPKA_HUMAN IPKA_HUMAN]] Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains. 
== 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/2vo7_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.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=2vo7 ConSurf].
<div style="clear:both"></div>
<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.

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 2vo7" style="background-color:#fffaf0;"></div>

==See Also==
*[[CAMP-dependent protein kinase 3D structures|CAMP-dependent protein kinase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bovin]]
[[Category: Large Structures]]
[[Category: CAMP-dependent protein kinase]]
[[Category: Aherne, G W]]
[[Category: Caldwell, J J]]
[[Category: Collins, I]]
[[Category: Davies, T G]]
[[Category: Donald, A]]
[[Category: Garrett, M D]]
[[Category: Hunter, L K]]
[[Category: McHardy, T]]
[[Category: Raynaud, F I]]
[[Category: Rowlands, M G]]
[[Category: Ruddle, R]]
[[Category: Taylor, K]]
[[Category: Verdonk, M]]
[[Category: Workman, P]]
[[Category: Atp-binding]]
[[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]]