3mvj

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 1: Line 1:
-
{{STRUCTURE_3mvj| PDB=3mvj | SCENE= }}
+
==Human cyclic AMP-dependent protein kinase PKA inhibitor complex==
-
===Human cyclic AMP-dependent protein kinase PKA inhibitor complex===
+
<StructureSection load='3mvj' size='340' side='right' caption='[[3mvj]], [[Resolution|resolution]] 2.49&Aring;' scene=''>
-
{{ABSTRACT_PUBMED_20481595}}
+
== Structural highlights ==
 +
<table><tr><td colspan='2'>[[3mvj]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MVJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3MVJ FirstGlance]. <br>
 +
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=XFE:(3R)-1-(5-METHYL-7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PYRROLIDIN-3-AMINE'>XFE</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">[[3mv5|3mv5]], [[3mvh|3mvh]]</td></tr>
 +
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PKA, PKACA, PRKACA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=3mvj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3mvj OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3mvj RCSB], [http://www.ebi.ac.uk/pdbsum/3mvj PDBsum]</span></td></tr>
 +
</table>
 +
== 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/mv/3mvj_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/chain_selection.php?pdb_ID=2ata ConSurf].
 +
<div style="clear:both"></div>
 +
<div style="background-color:#fffaf0;">
 +
== Publication Abstract from PubMed ==
 +
This paper describes the design and synthesis of novel, ATP-competitive Akt inhibitors from an elaborated 3-aminopyrrolidine scaffold. Key findings include the discovery of an initial lead that was modestly selective and medicinal chemistry optimization of that lead to provide more selective analogues. Analysis of the data suggested that highly lipophilic analogues would likely suffer from poor overall properties. Central to the discussion is the concept of optimization of lipophilic efficiency and the ability to balance overall druglike propeties with the careful control of lipophilicity in the lead series. Discovery of the nonracemic amide series and subsequent modification produced an advanced analogue that performed well in advanced preclinical assays, including xenograft tumor growth inhibition studies, and this analogue was nominated for clinical development.
-
==Function==
+
Design of Selective, ATP-Competitive Inhibitors of Akt.,Freeman-Cook KD, Autry C, Borzillo G, Gordon D, Barbacci-Tobin E, Bernardo V, Briere D, Clark T, Corbett M, Jakubczak J, Kakar S, Knauth E, Lippa B, Luzzio MJ, Mansour M, Martinelli G, Marx M, Nelson K, Pandit J, Rajamohan F, Robinson S, Subramanyam C, Wei L, Wythes M, Morris J J Med Chem. 2010 May 19. PMID:20481595<ref>PMID:20481595</ref>
-
[[http://www.uniprot.org/uniprot/KAPCA_HUMAN KAPCA_HUMAN]] 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). Phosphorylates APOBEC3G and AICDA.<ref>PMID:15016832</ref> <ref>PMID:15642694</ref> <ref>PMID:15905176</ref> <ref>PMID:17565987</ref> <ref>PMID:17693412</ref> <ref>PMID:17333334</ref> <ref>PMID:20356841</ref> <ref>PMID:19949837</ref> <ref>PMID:21514275</ref> <ref>PMID:21812984</ref> <ref>PMID:21423175</ref> [[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.
+
-
==About this Structure==
+
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-
[[3mvj]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3MVJ OCA].
+
</div>
==See Also==
==See Also==
*[[CAMP-dependent protein kinase|CAMP-dependent protein kinase]]
*[[CAMP-dependent protein kinase|CAMP-dependent protein kinase]]
-
 
+
== References ==
-
==Reference==
+
<references/>
-
<ref group="xtra">PMID:020481595</ref><references group="xtra"/><references/>
+
__TOC__
 +
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: CAMP-dependent protein kinase]]
[[Category: CAMP-dependent protein kinase]]
-
[[Category: Pandit, J.]]
+
[[Category: Pandit, J]]
-
[[Category: Vajdos, F.]]
+
[[Category: Vajdos, F]]
[[Category: Kinase inhibitor]]
[[Category: Kinase inhibitor]]
[[Category: Transferase]]
[[Category: Transferase]]

Revision as of 15:07, 18 December 2014

Human cyclic AMP-dependent protein kinase PKA inhibitor complex

3mvj, resolution 2.49Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3mvj"
Personal tools