Top ▲

beta adrenergic receptor kinase 1

Click here for help

Target id: 1466

Nomenclature: beta adrenergic receptor kinase 1

Abbreviated Name: GRK2

Family: Beta-adrenergic receptor kinases (βARKs)

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 689 11q13.2 GRK2 G protein-coupled receptor kinase 2
Mouse - 689 19 3.98 cM Grk2 G protein-coupled receptor kinase 2
Rat - 689 1q43 Grk2 G protein-coupled receptor kinase 2
Previous and Unofficial Names Click here for help
ADRGK1 | BARK1 | GRK2 | G-protein-coupled receptor kinase 2 | beta-AR kinase-1 | betaARK1 | adrenergic, beta, receptor kinase 1 | ADRBK1 | Adrbk1 | adrenergic
Database Links Click here for help
Alphafold P25098 (Hs), Q99MK8 (Mm), P26817 (Rn)
BRENDA 2.7.11.15
CATH/Gene3D 2.30.29.30
ChEMBL Target CHEMBL4079 (Hs), CHEMBL3711486 (Mm), CHEMBL4105719 (Rn)
Ensembl Gene ENSG00000173020 (Hs), ENSMUSG00000024858 (Mm), ENSRNOG00000018985 (Rn)
Entrez Gene 156 (Hs), 110355 (Mm), 25238 (Rn)
Human Protein Atlas ENSG00000173020 (Hs)
KEGG Enzyme 2.7.11.15
KEGG Gene hsa:156 (Hs), mmu:110355 (Mm), rno:25238 (Rn)
OMIM 109635 (Hs)
Pharos P25098 (Hs)
RefSeq Nucleotide NM_001619 (Hs), NM_130863 (Mm), NM_012776 (Rn)
RefSeq Protein NP_001610 (Hs), NP_570933 (Mm), NP_036908 (Rn)
SynPHARM 81500 (in complex with balanol)
UniProtKB P25098 (Hs), Q99MK8 (Mm), P26817 (Rn)
Wikipedia GRK2 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  G Protein-Coupled Receptor Kinase 2 (GRK2)
PDB Id:  1YM7
Resolution:  4.5Å
Species:  Human
References:  8
Image of receptor 3D structure from RCSB PDB
Description:  Human G Protein-Coupled Receptor Kinase 2 in Complex with Soluble Gbetagamma Subunits and Paroxetine
PDB Id:  3V5W
Ligand:  paroxetine
Resolution:  2.07Å
Species:  Human
References:  12
Image of receptor 3D structure from RCSB PDB
Description:  Human GRK2 in complex with Gβγ subunits and balanol (co-crystal).
PDB Id:  3KRX
Ligand:  balanol
Resolution:  3.1Å
Species:  Human
References:  11
Enzyme Reaction Click here for help
EC Number: 2.7.11.15

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CCG258747 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 7.7 pIC50 2
⤷ pIC50 7.7 (IC50 1.8x10-8 M) [2]
balanol Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.4 pIC50 11
⤷ pIC50 7.4 (IC50 4.2x10-8 M) [11]
Description: Inhibition of tubulin phosphorylation by balanol.
compound 101 [PMID: 21596927] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.3 pIC50 13
⤷ pIC50 7.3 (IC50 5.4x10-8 M) [13]
compound 1o [PMID: 24210504] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 6.3 pIC50 5
⤷ pIC50 6.3 (IC50 4.6x10-7 M) [5]
Inhibitor Comments
A component of agonist-induced desensitisation of the μ opioid receptor is reversed by compound 101 inhibition of GRK2/3 [10].
EMD Millipore KinaseProfilerTM screen/Reaction Biology Kinase HotspotSM screen Click here for help
A screen profiling 158 kinase inhibitors (Calbiochem Protein Kinase Inhibitor Library I and II, catalogue numbers 539744 and 539745) for their inhibitory activity at 1µM and 10µM against 234 human recombinant kinases using the EMD Millipore KinaseProfilerTM service.

A screen profiling the inhibitory activity of 178 commercially available kinase inhibitors at 0.5µM against a panel of 300 recombinant protein kinases using the Reaction Biology Corporation Kinase HotspotSM platform.

http://www.millipore.com/techpublications/tech1/pf3036
http://www.reactionbiology.com/webapps/main/pages/kinase.aspx

Reference: ...1
Key to terms and symbols Click column headers to sort
Target used in screen: nd/GRK2
Ligand Sp. Type Action % Activity remaining at 0.5µM % Activity remaining at 1µM % Activity remaining at 10µM
staurosporine Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 56.8
aloisine A Small molecule or natural product Hs Inhibitor Inhibition 76.5
aloisine Small molecule or natural product Hs Inhibitor Inhibition 78.5
KU-55933 Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 79.0
ATM/ATR kinase inhibitor Small molecule or natural product Hs Inhibitor Inhibition 79.5
dorsomorphin Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 81.8
aminopurvalanol A Small molecule or natural product Hs Inhibitor Inhibition 83.0
AGL 2043 Small molecule or natural product Hs Inhibitor Inhibition 83.7
AG 1024 Small molecule or natural product Hs Inhibitor Inhibition 83.7
aurora kinase inhibitor III Small molecule or natural product Ligand has a PDB structure Hs Inhibitor Inhibition 84.7
Displaying the top 10 most potent ligands  View all ligands in screen »
Immunopharmacology Comments
GRK2 (βARK1) expression and activity are downregulated in lymphocytes from RA patients [9]. In healthy leukocytes, pro-inflammatory cytokines reduce GRK2 expression
Immuno Process Associations
Immuno Process:  Barrier integrity
Immuno Process:  Antigen presentation
Immuno Process:  Chemotaxis & migration
Immuno Process:  Cytokine production & signalling
Physiological Consequences of Altering Gene Expression Click here for help
Increased GRK2 protein and mRNA levels are associated with increased myocardial GRK activity in human heart failure.
Species:  Human
Tissue:  Cardiac tissue.
Technique:  qPCR, Western blotting.
References:  3-4,14-15
Germline ablation of the GRK2 gene produces embryonic lethality, with embryos displaying cardiac abnormalities.
Species:  Mouse
Tissue: 
Technique:  Gene knock-out.
References:  7
Physiological Consequences of Altering Gene Expression Comments
The essential role of GRK2 in embryonic development may not be due to its GPCR kinase activity, as mice with cardiac-specific ablation of GRK2 develop normally [6].

References

Show »

1. Anastassiadis T, Deacon SW, Devarajan K, Ma H, Peterson JR. (2011) Comprehensive assay of kinase catalytic activity reveals features of kinase inhibitor selectivity. Nat Biotechnol, 29 (11): 1039-45. [PMID:22037377]

2. Bouley RA, Weinberg ZY, Waldschmidt HV, Yen YC, Larsen SD, Puthenveedu MA, Tesmer JJG. (2020) A New Paroxetine-Based GRK2 Inhibitor Reduces Internalization of the μ-Opioid Receptor. Mol Pharmacol, 97 (6): 392-401. [PMID:32234810]

3. Bristow MR, Hershberger RE, Port JD, Gilbert EM, Sandoval A, Rasmussen R, Cates AE, Feldman AM. (1990) Beta-adrenergic pathways in nonfailing and failing human ventricular myocardium. Circulation, 82 (2 Suppl): I12-25. [PMID:2164894]

4. Bristow MR, Kantrowitz NE, Ginsburg R, Fowler MB. (1985) Beta-adrenergic function in heart muscle disease and heart failure. J Mol Cell Cardiol, 17 Suppl 2: 41-52. [PMID:2863387]

5. Cho SY, Lee BH, Jung H, Yun CS, Ha JD, Kim HR, Chae CH, Lee JH, Seo HW, Oh KS. (2013) Design and synthesis of novel 3-(benzo[d]oxazol-2-yl)-5-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)pyridin-2-amine derivatives as selective G-protein-coupled receptor kinase-2 and -5 inhibitors. Bioorg Med Chem Lett, 23 (24): 6711-6. [PMID:24210504]

6. Dorn 2nd GW. (2009) GRK mythology: G-protein receptor kinases in cardiovascular disease. J Mol Med, 87 (5): 455-63. [PMID:19229505]

7. Jaber M, Koch WJ, Rockman H, Smith B, Bond RA, Sulik KK, Ross Jr J, Lefkowitz RJ, Caron MG, Giros B. (1996) Essential role of beta-adrenergic receptor kinase 1 in cardiac development and function. Proc Natl Acad Sci USA, 93 (23): 12974-9. [PMID:8917529]

8. Lodowski DT, Barnhill JF, Pyskadlo RM, Ghirlando R, Sterne-Marr R, Tesmer JJ. (2005) The role of G beta gamma and domain interfaces in the activation of G protein-coupled receptor kinase 2. Biochemistry, 44 (18): 6958-70. [PMID:15865441]

9. Lombardi MS, Kavelaars A, Schedlowski M, Bijlsma JW, Okihara KL, Van de Pol M, Ochsmann S, Pawlak C, Schmidt RE, Heijnen CJ. (1999) Decreased expression and activity of G-protein-coupled receptor kinases in peripheral blood mononuclear cells of patients with rheumatoid arthritis. FASEB J, 13 (6): 715-25. [PMID:10094932]

10. Lowe JD, Sanderson HS, Cooke AE, Ostovar M, Tsisanova E, Withey SL, Chavkin C, Husbands SM, Kelly E, Henderson G et al.. (2015) Role of G Protein-Coupled Receptor Kinases 2 and 3 in μ-Opioid Receptor Desensitization and Internalization. Mol Pharmacol, 88 (2): 347-56. [PMID:26013542]

11. Tesmer JJ, Tesmer VM, Lodowski DT, Steinhagen H, Huber J. (2010) Structure of human G protein-coupled receptor kinase 2 in complex with the kinase inhibitor balanol. J Med Chem, 53 (4): 1867-70. [PMID:20128603]

12. Thal DM, Homan KT, Chen J, Wu EK, Hinkle PM, Huang ZM, Chuprun JK, Song J, Gao E, Cheung JY et al.. (2012) Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility. ACS Chem Biol, 7 (11): 1830-9. [PMID:22882301]

13. Thal DM, Yeow RY, Schoenau C, Huber J, Tesmer JJ. (2011) Molecular mechanism of selectivity among G protein-coupled receptor kinase 2 inhibitors. Mol Pharmacol, 80 (2): 294-303. [PMID:21596927]

14. Ungerer M, Böhm M, Elce JS, Erdmann E, Lohse MJ. (1993) Altered expression of beta-adrenergic receptor kinase and beta 1-adrenergic receptors in the failing human heart. Circulation, 87 (2): 454-63. [PMID:8381058]

15. Ungerer M, Parruti G, Böhm M, Puzicha M, DeBlasi A, Erdmann E, Lohse MJ. (1994) Expression of beta-arrestins and beta-adrenergic receptor kinases in the failing human heart. Circ Res, 74 (2): 206-13. [PMID:8293560]

How to cite this page

Beta-adrenergic receptor kinases (βARKs): beta adrenergic receptor kinase 1. Last modified on 04/06/2020. Accessed on 18/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=1466.