| Structural highlights
3v5w is a 3 chain structure with sequence from Bos taurus and Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , |
| Related: | 3cik, 3krw, 3pvu, 3pvw |
| Gene: | ADRBK1, BARK, BARK1, GRK2 (Homo sapiens), GNB1 (Bos taurus), GNG2 (Bos taurus) |
| Activity: | [Beta-adrenergic-receptor_kinase [Beta-adrenergic-receptor] kinase], with EC number 2.7.11.15 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
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] [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. [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.
Publication Abstract from PubMed
G protein-coupled receptor kinase 2 (GRK2) is a well-established therapeutic target for the treatment of heart failure. Herein we identify the selective serotonin reuptake inhibitor (SSRI) paroxetine as a selective inhibitor of GRK2 activity both in vitro and in living cells. In the crystal structure of the GRK2.paroxetine-Gbetagamma complex, paroxetine binds in the active site of GRK2 and stabilizes the kinase domain in a novel conformation in which a unique regulatory loop forms part of the ligand binding site. Isolated cardiomyocytes show increased isoproterenol-induced shortening and contraction amplitude in the presence of paroxetine, and pretreatment of mice with paroxetine before isoproterenol significantly increases left ventricular inotropic reserve in vivo with no significant effect on heart rate. Neither is observed in the presence of the SSRI fluoxetine. Our structural and functional results validate a widely available drug as a selective chemical probe for GRK2 and represent a starting point for the rational design of more potent and specific GRK2 inhibitors.
Paroxetine Is a Direct Inhibitor of G Protein-Coupled Receptor Kinase 2 and Increases Myocardial Contractility.,Thal DM, Homan KT, Chen J, Wu EK, Hinkle PM, Huang ZM, Chuprun JK, Song J, Gao E, Cheung JY, Sklar LA, Koch WJ, Tesmer JJ ACS Chem Biol. 2012 Aug 21. PMID:22882301[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
- ↑ Thal DM, Homan KT, Chen J, Wu EK, Hinkle PM, Huang ZM, Chuprun JK, Song J, Gao E, Cheung JY, Sklar LA, Koch WJ, Tesmer JJ. Paroxetine Is a Direct Inhibitor of G Protein-Coupled Receptor Kinase 2 and Increases Myocardial Contractility. ACS Chem Biol. 2012 Aug 21. PMID:22882301 doi:http://dx.doi.org/10.1021/cb3003013
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