PDBsum entry 3v5w

Transferase/transferase inhibitor

PDB id: 3v5w

Contents

Protein chains

623 a.a.

339 a.a.

57 a.a.

Ligands

8PR

Metals

_MG

Waters ×296

PDB id:

3v5w

Name:

Transferase/transferase inhibitor

Title:

Human g protein-coupled receptor kinase 2 in complex with soluble gbetagamma subunits and paroxetine

Structure:

G-protein coupled receptor kinase 2. Chain: a. Synonym: beta-ark-1, beta-adrenergic receptor kinase 1. Engineered: yes. Guanine nucleotide-binding protein g(i)/g(s)/g(t) subunit beta-1. Chain: b. Synonym: transducin beta chain 1. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: adrbk1, bark, bark1, grk2. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Bos taurus. Bovine. Organism_taxid: 9913.

Resolution:

2.07Å R-factor: 0.196 R-free: 0.247

Authors:

D.M.Thal,J.J.G.Tesmer

Key ref:

D.M.Thal et al. (2012). Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility. Acs Chem Biol, 7, 1830-1839. PubMed id: 22882301 DOI: 10.1021/cb3003013

Date:

17-Dec-11 Release date: 26-Sep-12

Protein chain

P25098  (ARBK1_HUMAN) -  Beta-adrenergic receptor kinase 1 from Homo sapiens

Seq: 689 a.a.

Struc: 623 a.a.

Protein chain

P62871  (GBB1_BOVIN) -  Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 from Bos taurus

Seq: 340 a.a.

Struc: 339 a.a.

Protein chain

P63212  (GBG2_BOVIN) -  Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 from Bos taurus

Seq: 71 a.a.

Struc: 57 a.a.

Enzyme reactions

• Enzyme class: Chain A: E.C.2.7.11.15 - [beta-adrenergic-receptor] kinase.
• Reaction: [beta-adrenergic receptor] + ATP = [beta-adrenergic receptor]-phosphate + ADP + H⁺

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1021/cb3003013

Acs Chem Biol 7:1830-1839 (2012)

PubMed id: 22882301

Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility.

D.M.Thal, K.T.Homan, J.Chen, E.K.Wu, P.M.Hinkle, Z.M.Huang, J.K.Chuprun, J.Song, E.Gao, J.Y.Cheung, L.A.Sklar, W.J.Koch, J.J.Tesmer.

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.