1xha

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[[Image:1xha.gif|left|200px]]
 
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==Crystal Structures of Protein Kinase B Selective Inhibitors in Complex with Protein Kinase A and Mutants==
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The line below this paragraph, containing "STRUCTURE_1xha", creates the "Structure Box" on the page.
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<StructureSection load='1xha' size='340' side='right'caption='[[1xha]], [[Resolution|resolution]] 2.46&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[1xha]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1XHA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1XHA FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.46&#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=R68:N-{4-[(4-{3-[(2R)-3,3-DIMETHYLPIPERIDIN-2-YL]-2-FLUORO-6-HYDROXYBENZOYL}BENZOYL)AMINO]AZEPAN-3-YL}ISONICOTINAMIDE'>R68</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
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{{STRUCTURE_1xha| PDB=1xha | SCENE= }}
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1xha FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1xha OCA], [https://pdbe.org/1xha PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1xha RCSB], [https://www.ebi.ac.uk/pdbsum/1xha PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1xha ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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).
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/xh/1xha_consurf.spt"</scriptWhenChecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</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=1xha ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Protein kinase B (PKB)-selective inhibitors were designed, synthesized, and cocrystallized using the AGC kinase family protein kinase A (PKA, often called cAMP-dependent protein kinase); PKA has been used as a surrogate for other members of this family and indeed for protein kinases in general. The high homology between PKA and PKB includes very similar ATP binding sites and hence similar binding pockets for inhibitors, with only few amino acids that differ between the two kinases. A series of these sites were mutated in PKA in order to improve the surrogate model for a design of PKB-selective inhibitors. Namely, the PKA to PKB exchanges F187L and Q84E enable the design of the selective inhibitors described herein which mimic ATP but extend further into a site not occupied by ATP. In this pocket, selectivity over PKA can be achieved by the introduction of bulkier substituents. Analysis of the cocrystal structures and binding studies were performed to rationalize the selectivity and improve the design.
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'''Crystal Structures of Protein Kinase B Selective Inhibitors in Complex with Protein Kinase A and Mutants'''
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Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants.,Breitenlechner CB, Friebe WG, Brunet E, Werner G, Graul K, Thomas U, Kunkele KP, Schafer W, Gassel M, Bossemeyer D, Huber R, Engh RA, Masjost B J Med Chem. 2005 Jan 13;48(1):163-70. PMID:15634010<ref>PMID:15634010</ref>
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==Overview==
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Protein kinase B (PKB)-selective inhibitors were designed, synthesized, and cocrystallized using the AGC kinase family protein kinase A (PKA, often called cAMP-dependent protein kinase); PKA has been used as a surrogate for other members of this family and indeed for protein kinases in general. The high homology between PKA and PKB includes very similar ATP binding sites and hence similar binding pockets for inhibitors, with only few amino acids that differ between the two kinases. A series of these sites were mutated in PKA in order to improve the surrogate model for a design of PKB-selective inhibitors. Namely, the PKA to PKB exchanges F187L and Q84E enable the design of the selective inhibitors described herein which mimic ATP but extend further into a site not occupied by ATP. In this pocket, selectivity over PKA can be achieved by the introduction of bulkier substituents. Analysis of the cocrystal structures and binding studies were performed to rationalize the selectivity and improve the design.
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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1XHA is a [[Protein complex]] 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=1XHA OCA].
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</div>
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<div class="pdbe-citations 1xha" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants., Breitenlechner CB, Friebe WG, Brunet E, Werner G, Graul K, Thomas U, Kunkele KP, Schafer W, Gassel M, Bossemeyer D, Huber R, Engh RA, Masjost B, J Med Chem. 2005 Jan 13;48(1):163-70. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/15634010 15634010]
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*[[CAMP-dependent protein kinase 3D structures|CAMP-dependent protein kinase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Bos taurus]]
[[Category: Bos taurus]]
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Large Structures]]
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[[Category: Protein complex]]
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[[Category: Synthetic construct]]
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[[Category: Bossemeyer, D.]]
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[[Category: Bossemeyer D]]
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[[Category: Breitenlechner, C B.]]
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[[Category: Breitenlechner CB]]
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[[Category: Brunet, E.]]
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[[Category: Brunet E]]
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[[Category: Engh, R A.]]
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[[Category: Engh RA]]
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[[Category: Friebe, W G.]]
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[[Category: Friebe W-G]]
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[[Category: Gassel, M.]]
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[[Category: Gassel M]]
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[[Category: Graul, K.]]
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[[Category: Graul K]]
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[[Category: Huber, R.]]
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[[Category: Huber R]]
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[[Category: Kuenkele, K P.]]
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[[Category: Kuenkele K-P]]
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[[Category: Masjost, B.]]
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[[Category: Masjost B]]
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[[Category: Schaefer, W.]]
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[[Category: Schaefer W]]
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[[Category: Thomas, U.]]
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[[Category: Thomas U]]
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[[Category: Werner, G.]]
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[[Category: Werner G]]
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[[Category: Balanol derivative]]
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[[Category: Kinase-inhibitor-complex]]
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[[Category: Pka]]
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[[Category: Serine/threonine-protein kinase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 15:01:42 2008''
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Crystal Structures of Protein Kinase B Selective Inhibitors in Complex with Protein Kinase A and Mutants

PDB ID 1xha

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