3V5W

Human G Protein-Coupled Receptor Kinase 2 in Complex with Soluble Gbetagamma Subunits and Paroxetine

Summary for 3V5W

• Entry DOI: 10.2210/pdb3v5w/pdb
• Related: 3CIK 3KRW 3PVU 3PVW
• Descriptor: G-protein coupled receptor kinase 2, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (6 entities in total)
• Functional Keywords: inhibitor complex, protein kinase, beta propeller, rgs homology domain, pleckstrin homology domain, kinase, signal transduction, peripheral membrane protein, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cell membrane; Lipid-anchor; Cytoplasmic side (Potential): P63212
• Total number of polymer chains: 3
• Total formula weight: 126137.20

Authors

Thal, D.M.,Tesmer, J.J.G. (deposition date: 2011-12-17, release date: 2012-09-26, Last modification date: 2023-09-13)

Primary citation

Thal, D.M.,Homan, K.T.,Chen, J.,Wu, E.K.,Hinkle, P.M.,Huang, Z.M.,Chuprun, J.K.,Song, J.,Gao, E.,Cheung, J.Y.,Sklar, L.A.,Koch, W.J.,Tesmer, J.J.
Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility.
Acs Chem.Biol., 7:1830-1839, 2012

PubMed Abstract: 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-Gβγ 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.

PubMed: 22882301
DOI: 10.1021/cb3003013

Experimental method

X-RAY DIFFRACTION (2.07 Å)