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| | ==Crystal Structure of RIIbeta(108-402) bound to HE33, a N6 di-propyl substituted cAMP analog== | | ==Crystal Structure of RIIbeta(108-402) bound to HE33, a N6 di-propyl substituted cAMP analog== |
| - | <StructureSection load='4jva' size='340' side='right' caption='[[4jva]], [[Resolution|resolution]] 2.50Å' scene=''> | + | <StructureSection load='4jva' size='340' side='right'caption='[[4jva]], [[Resolution|resolution]] 2.50Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4jva]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JVA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4JVA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4jva]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4JVA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4JVA FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=1OR:(2R,4AR,6R,7R,7AS)-6-[6-(DIPROPYLAMINO)-9H-PURIN-9-YL]TETRAHYDRO-4H-FURO[3,2-D][1,3,2]DIOXAPHOSPHININE-2,7-DIOL+2-OXIDE'>1OR</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1OR:(2R,4AR,6R,7R,7AS)-6-[6-(DIPROPYLAMINO)-9H-PURIN-9-YL]TETRAHYDRO-4H-FURO[3,2-D][1,3,2]DIOXAPHOSPHININE-2,7-DIOL+2-OXIDE'>1OR</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1cx4|1cx4]], [[4jv4|4jv4]]</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=4jva FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jva OCA], [https://pdbe.org/4jva PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4jva RCSB], [https://www.ebi.ac.uk/pdbsum/4jva PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4jva ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Prkar2b ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10116 Buffalo rat])</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=4jva FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4jva OCA], [http://pdbe.org/4jva PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4jva RCSB], [http://www.ebi.ac.uk/pdbsum/4jva PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4jva ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/KAP3_RAT KAP3_RAT]] Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Type II regulatory chains mediate membrane association by binding to anchoring proteins, including the MAP2 kinase. | + | [https://www.uniprot.org/uniprot/KAP3_RAT KAP3_RAT] Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Type II regulatory chains mediate membrane association by binding to anchoring proteins, including the MAP2 kinase. |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[CAMP-dependent protein kinase|CAMP-dependent protein kinase]] | + | *[[CAMP-dependent protein kinase 3D structures|CAMP-dependent protein kinase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Buffalo rat]] | + | [[Category: Large Structures]] |
| - | [[Category: Brown, S H.J]] | + | [[Category: Rattus norvegicus]] |
| - | [[Category: Cheng, C Y]] | + | [[Category: Brown SHJ]] |
| - | [[Category: Cottam, H]] | + | [[Category: Cheng CY]] |
| - | [[Category: Saldanha, A S]] | + | [[Category: Cottam H]] |
| - | [[Category: Sankaran, B]] | + | [[Category: Saldanha AS]] |
| - | [[Category: Taylor, S S]] | + | [[Category: Sankaran B]] |
| - | [[Category: Wu, J]] | + | [[Category: Taylor SS]] |
| - | [[Category: Camp-dependent protein kinase]]
| + | [[Category: Wu J]] |
| - | [[Category: Cyclic nucleotide analog]]
| + | |
| - | [[Category: Fluorescence anisotropy]]
| + | |
| - | [[Category: Isoform selectivity]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
| + | |
| Structural highlights
Function
KAP3_RAT Regulatory subunit of the cAMP-dependent protein kinases involved in cAMP signaling in cells. Type II regulatory chains mediate membrane association by binding to anchoring proteins, including the MAP2 kinase.
Publication Abstract from PubMed
Cyclic AMP (cAMP) is a ubiquitous second messenger that regulates many proteins, most notably cAMP-dependent protein kinase (PKA). PKA holoenzymes (comprised of two catalytic (C) and two regulatory (R) subunits) regulate a wide variety of cellular processes, and its functional diversity is amplified by the presence of four R-subunit isoforms, RIalpha, RIbeta, RIIalpha, and RIIbeta. Although these isoforms all respond to cAMP, they are functionally nonredundant and exhibit different biochemical properties. In order to understand the functional differences between these isoforms, we screened cAMP derivatives for their ability to selectively activate RI and RII PKA holoenzymes using a fluorescence anisotropy assay. Our results indicate that RIalpha holoenzymes are selectively activated by C8-substituted analogs and RIIbeta holoenzymes by N6-substituted analogs, where HE33 is the most prominent RII activator. We also solved the crystal structures of both RIalpha and RIIbeta bound to HE33. The RIIbeta structure shows the bulky aliphatic substituent of HE33 is fully encompassed by a pocket comprising of hydrophobic residues. RIalpha lacks this hydrophobic lining in Domain A, and the side chains are displaced to accommodate the HE33 dipropyl groups. Comparison between cAMP-bound structures reveals that RIIbeta, but not RIalpha, contains a cavity near the N6 site. This study suggests that the selective activation of RII over RI isoforms by N6 analogs is driven by the spatial and chemical constraints of Domain A and paves the way for the development of potent noncyclic nucleotide activators to specifically target PKA iso-holoenyzmes.
Implementing Fluorescence Anisotropy Screening and Crystallographic Analysis to Define PKA Isoform-Selective Activation by cAMP Analogs.,Brown SH, Cheng CY, Saldanha SA, Wu J, Cottam HB, Sankaran B, Taylor SS ACS Chem Biol. 2013 Sep 10. PMID:23978166[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Brown SH, Cheng CY, Saldanha SA, Wu J, Cottam HB, Sankaran B, Taylor SS. Implementing Fluorescence Anisotropy Screening and Crystallographic Analysis to Define PKA Isoform-Selective Activation by cAMP Analogs. ACS Chem Biol. 2013 Sep 10. PMID:23978166 doi:10.1021/cb400247t
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