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| | ==Crystal structure of G protein-coupled receptor kinase 2 in complex with a a rationally designed paroxetine derivative== | | ==Crystal structure of G protein-coupled receptor kinase 2 in complex with a a rationally designed paroxetine derivative== |
| - | <StructureSection load='4mk0' size='340' side='right' caption='[[4mk0]], [[Resolution|resolution]] 2.40Å' scene=''> | + | <StructureSection load='4mk0' size='340' side='right'caption='[[4mk0]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4mk0]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Bovin Bovin] and [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MK0 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4MK0 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4mk0]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4MK0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4MK0 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=29X:5-{[(3S,4R)-4-(4-FLUOROPHENYL)PIPERIDIN-3-YL]METHOXY}-1H-ISOINDOL-1-ONE'>29X</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=29X:5-{[(3S,4R)-4-(4-FLUOROPHENYL)PIPERIDIN-3-YL]METHOXY}-1H-ISOINDOL-1-ONE'>29X</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3v5w|3v5w]], [[4l9i|4l9i]], [[1omw|1omw]]</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=4mk0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mk0 OCA], [https://pdbe.org/4mk0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4mk0 RCSB], [https://www.ebi.ac.uk/pdbsum/4mk0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4mk0 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ADRBK1, BARK, BARK1, GRK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), GNB1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9913 BOVIN]), GNG2 ([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/[Beta-adrenergic-receptor]_kinase [Beta-adrenergic-receptor] kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.15 2.7.11.15] </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=4mk0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4mk0 OCA], [http://pdbe.org/4mk0 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4mk0 RCSB], [http://www.ebi.ac.uk/pdbsum/4mk0 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4mk0 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/ARBK1_HUMAN ARBK1_HUMAN]] Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner.<ref>PMID:19306925</ref> [[http://www.uniprot.org/uniprot/GBG2_BOVIN GBG2_BOVIN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. [[http://www.uniprot.org/uniprot/GBB1_BOVIN GBB1_BOVIN]] Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. | + | [https://www.uniprot.org/uniprot/ARBK1_HUMAN ARBK1_HUMAN] Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner.<ref>PMID:19306925</ref> |
| | <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== |
| - | *[[Transducin|Transducin]] | + | *[[Beta adrenergic receptor kinase 3D structures|Beta adrenergic receptor kinase 3D structures]] |
| | + | *[[Transducin 3D structures|Transducin 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bovin]] | + | [[Category: Bos taurus]] |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Homan, K T]] | + | [[Category: Large Structures]] |
| - | [[Category: Tesmer, J J.G]] | + | [[Category: Homan KT]] |
| - | [[Category: Atp binding]] | + | [[Category: Tesmer JJG]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Inhibitor complex]]
| + | |
| - | [[Category: Peripheral membrane protein]]
| + | |
| - | [[Category: Phosphorylation]]
| + | |
| - | [[Category: Protein kinase]]
| + | |
| - | [[Category: Signaling protein-inhibitor complex]]
| + | |
| Structural highlights
Function
ARBK1_HUMAN Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner.[1]
Publication Abstract from PubMed
Recently we identified the serotonin reuptake inhibitor paroxetine as an inhibitor of G protein-coupled receptor kinase 2 (GRK2) that improves cardiac performance in live animals. Paroxetine exhibits up to 50-fold selectivity for GRK2 versus other GRKs. A better understanding of the molecular basis of this selectivity is important for the development of even more selective and potent small molecule therapeutics and chemical genetic probes. We first sought to understand the molecular mechanisms underlying paroxetine selectivity among GRKs. We directly measured the KD for paroxetine and assessed its mechanism of inhibition for each of the GRK subfamilies and then determined the atomic structure of its complex with GRK1, the most weakly inhibited GRK tested. Our results suggest that the selectivity of paroxetine for GRK2 largely reflects its lower affinity for adenine nucleotides. Thus, stabilization of off-pathway conformational states unique to GRK2 will likely be key for the development of even more selective inhibitors. Next, we designed a benzolactam derivative of paroxetine that has optimized interactions with the hinge of the GRK2 kinase domain. The crystal structure of this compound in complex with GRK2 confirmed the predicted interactions. Although the benzolactam derivative did not significantly alter potency of inhibition among GRKs, it exhibited 20-fold lower inhibition of serotonin reuptake. However, there was an associated increase in the potency for inhibition of other AGC kinases, suggesting that the unconventional hydrogen bond formed by the benzodioxole ring of paroxetine is better accommodated by GRKs.
Structural and functional analysis of g protein-coupled receptor kinase inhibition by paroxetine and a rationally designed analog.,Homan KT, Wu E, Wilson MW, Singh P, Larsen SD, Tesmer JJ Mol Pharmacol. 2014 Feb;85(2):237-48. doi: 10.1124/mol.113.089631. Epub 2013 Nov , 12. PMID:24220010[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Aziziyeh AI, Li TT, Pape C, Pampillo M, Chidiac P, Possmayer F, Babwah AV, Bhattacharya M. Dual regulation of lysophosphatidic acid (LPA1) receptor signalling by Ral and GRK. Cell Signal. 2009 Jul;21(7):1207-17. doi: 10.1016/j.cellsig.2009.03.011. Epub, 2009 Mar 21. PMID:19306925 doi:10.1016/j.cellsig.2009.03.011
- ↑ Homan KT, Wu E, Wilson MW, Singh P, Larsen SD, Tesmer JJ. Structural and functional analysis of g protein-coupled receptor kinase inhibition by paroxetine and a rationally designed analog. Mol Pharmacol. 2014 Feb;85(2):237-48. doi: 10.1124/mol.113.089631. Epub 2013 Nov , 12. PMID:24220010 doi:http://dx.doi.org/10.1124/mol.113.089631
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