View source for 6e9l


==Crystal structure of Protein Kinase A in complex with the PKI peptide and a pyridinylbenzamide based inhibitor==
<StructureSection load='6e9l' size='340' side='right' caption='[[6e9l]], [[Resolution|resolution]] 2.80&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6e9l]] 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=6E9L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6E9L FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=J0P:N-[(2,3-dihydro-1,4-benzodioxin-5-yl)methyl]-4-(pyridin-4-yl)benzamide'>J0P</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">[[6e99|6e99]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PRKACA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 BOVIN])</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://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6e9l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6e9l OCA], [http://pdbe.org/6e9l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6e9l RCSB], [http://www.ebi.ac.uk/pdbsum/6e9l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6e9l 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. 
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Co-crystal structures of an early lead compound were obtained in PKA, ROCK1 and ROCK2. This provided critical structural information for medicinal chemistry to drive compound design. Aspartic acid residues 176 and 218 in ROCK2, which are glutamic acids in PKA, were targeted as residues to drive both potency and kinome selectivity. Introduction of a piperidin-3-ylmethanamine group to the compound series resulted in compound 58, a potent and selective dual ROCK inhibitor. Substitution (2-Cl, 2-NH2, 2-F, 3-F) of the pyridine hinge binding motif or replacement with pyrimidine afforded compounds with a clean CYP inhibition profile. Finally, compound 16, a potent and selective pan ROCK inhibitor, was shown to be efficacious in the retinal nerve fiber layer model after oral dosing.

Identification of Selective Dual ROCK1 and ROCK2 Inhibitors Using Structure Based Drug Design.,Hobson AD, Judge RA, Aguirre AL, Brown BS, Cui Y, Ding P, Dominguez E, DiGiammarino E, Egan DA, Freiberg GM, Gopalakrishnan SM, Harris CM, Honore MP, Kage KL, Kapecki NJ, Ling C, Ma J, Mack H, Mamo M, Maurus S, McRae B, Moore NS, Mueller BK, Mueller R, Namovic MT, Patel K, Pratt SD, Putman CB, Queeney KL, Sarris KK, Schaffter LM, Stoll VS, Vasudevan A, Wang L, Wang L, Wirthl W, Yach K J Med Chem. 2018 Nov 1. doi: 10.1021/acs.jmedchem.8b01098. PMID:30384606<ref>PMID:30384606</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6e9l" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Bovin]]
[[Category: CAMP-dependent protein kinase]]
[[Category: Hobson, A D]]
[[Category: Judge, R A]]
[[Category: Kinase]]
[[Category: Protein kinase some]]
[[Category: Transferase]]
[[Category: Transferase-transferase inhibitor complex]]