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==Protein Kinase A bound to (S)-2-(1H-Indol-3-yl)-1-[5-((E)-2-pyridin-4-yl-vinyl)-pyridin-3-yloxymethyl]-ethylamine==
==Protein Kinase A bound to (S)-2-(1H-Indol-3-yl)-1-[5-((E)-2-pyridin-4-yl-vinyl)-pyridin-3-yloxymethyl]-ethylamine==
<StructureSection load='2f7x' size='340' side='right' caption='[[2f7x]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
<StructureSection load='2f7x' size='340' side='right'caption='[[2f7x]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[2f7x]] is a 2 chain structure with sequence 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=2F7X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2F7X FirstGlance]. <br>
<table><tr><td colspan='2'>[[2f7x]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Sus_scrofa Sus scrofa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2F7X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2F7X FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4EA:(1S)-2-(1H-INDOL-3-YL)-1-[({5-[(E)-2-PYRIDIN-4-YLVINYL]PYRIDIN-3-YL}OXY)METHYL]ETHYLAMINE'>4EA</scene></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.9&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2f7e|2f7e]], [[1yds|1yds]], [[2f7z|2f7z]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4EA:(1S)-2-(1H-INDOL-3-YL)-1-[({5-[(E)-2-PYRIDIN-4-YLVINYL]PYRIDIN-3-YL}OXY)METHYL]ETHYLAMINE'>4EA</scene></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 Bos taurus])</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=2f7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2f7x OCA], [https://pdbe.org/2f7x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2f7x RCSB], [https://www.ebi.ac.uk/pdbsum/2f7x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2f7x ProSAT]</span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </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=2f7x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2f7x OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2f7x RCSB], [http://www.ebi.ac.uk/pdbsum/2f7x PDBsum]</span></td></tr>
</table>
</table>
== Function ==
== 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).  
[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 ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f7/2f7x_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/f7/2f7x_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
   </jmolCheckbox>
   </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/chain_selection.php?pdb_ID=2ata ConSurf].
</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=2f7x ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
A novel series of Akt/PKB inhibitors derived from a screening lead (1) has been prepared. The novel trans-3,4'-bispyridinylethylenes described herein are potent inhibitors of Akt/PKB with IC(50) values in the low double-digit nanomolar range against Akt1. Compound 2q shows excellent selectivity against distinct families of kinases such as tyrosine kinases and CAMK, and displays poor to modest selectivity against closely related kinases in the AGC and CMGC families. The cellular activities including inhibition of cell growth and phosphorylation of downstream target GSK3 are also described. The X-ray structure of compound 2q complexed with PKA in the ATP binding site was determined.
Discovery of trans-3,4'-bispyridinylethylenes as potent and novel inhibitors of protein kinase B (PKB/Akt) for the treatment of cancer: Synthesis and biological evaluation.,Li Q, Li T, Zhu GD, Gong J, Claibone A, Dalton C, Luo Y, Johnson EF, Shi Y, Liu X, Klinghofer V, Bauch JL, Marsh KC, Bouska JJ, Arries S, De Jong R, Oltersdorf T, Stoll VS, Jakob CG, Rosenberg SH, Giranda VL Bioorg Med Chem Lett. 2006 Mar 15;16(6):1679-85. Epub 2006 Jan 5. PMID:16403626<ref>PMID:16403626</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
==See Also==
</div>
*[[CAMP-dependent protein kinase 3D structures|CAMP-dependent protein kinase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Bos taurus]]
[[Category: Bos taurus]]
[[Category: Non-specific serine/threonine protein kinase]]
[[Category: Large Structures]]
[[Category: Arries, S]]
[[Category: Sus scrofa]]
[[Category: Bauch, J L]]
[[Category: Arries S]]
[[Category: Bouska, J J]]
[[Category: Bauch JL]]
[[Category: Claibone, A]]
[[Category: Bouska JJ]]
[[Category: Dalton, C]]
[[Category: Claibone A]]
[[Category: Giranda, V L]]
[[Category: Dalton C]]
[[Category: Gong, J]]
[[Category: De Jong R]]
[[Category: Jakob, C G]]
[[Category: Giranda VL]]
[[Category: Johnson, E F]]
[[Category: Gong J]]
[[Category: Jong, R De]]
[[Category: Jakob CG]]
[[Category: Klinghofer, V]]
[[Category: Johnson EF]]
[[Category: Li, Q]]
[[Category: Klinghofer V]]
[[Category: Li, T]]
[[Category: Li Q]]
[[Category: Liu, X]]
[[Category: Li T]]
[[Category: Luo, Y]]
[[Category: Liu X]]
[[Category: Marsh, K C]]
[[Category: Luo Y]]
[[Category: Oltersdorf, T]]
[[Category: Marsh KC]]
[[Category: Rosenberg, S H]]
[[Category: Oltersdorf T]]
[[Category: Shi, Y]]
[[Category: Rosenberg SH]]
[[Category: Stoll, V S]]
[[Category: Shi Y]]
[[Category: Zhu, G D]]
[[Category: Stoll VS]]
[[Category: Akt inhibitor]]
[[Category: Zhu GD]]
[[Category: Protein kinase some]]
[[Category: Transferase]]

Latest revision as of 12:21, 14 February 2024

Protein Kinase A bound to (S)-2-(1H-Indol-3-yl)-1-[5-((E)-2-pyridin-4-yl-vinyl)-pyridin-3-yloxymethyl]-ethylamineProtein Kinase A bound to (S)-2-(1H-Indol-3-yl)-1-[5-((E)-2-pyridin-4-yl-vinyl)-pyridin-3-yloxymethyl]-ethylamine

Structural highlights

2f7x is a 2 chain structure with sequence from Bos taurus and Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.9Å
Ligands:
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

2f7x, resolution 1.90Å

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