Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDTE82A)

• DOT Name: G protein-coupled receptor kinase 3 (GRK3)
• Synonyms: EC 2.7.11.15; Beta-adrenergic receptor kinase 2; Beta-ARK-2
• Gene Name: GRK3
• UniProt ID: ARBK2_HUMAN
• EC Number: 2.7.11.15
• Pfam ID: PF00169 ; PF00069 ; PF00615
• Sequence:
  MADLEAVLADVSYLMAMEKSKATPAARASKRIVLPEPSIRSVMQKYLAERNEITFDKIFN
  QKIGFLLFKDFCLNEINEAVPQVKFYEEIKEYEKLDNEEDRLCRSRQIYDAYIMKELLSC
  SHPFSKQAVEHVQSHLSKKQVTSTLFQPYIEEICESLRGDIFQKFMESDKFTRFCQWKNV
  ELNIHLTMNEFSVHRIIGRGGFGEVYGCRKADTGKMYAMKCLDKKRIKMKQGETLALNER
  IMLSLVSTGDCPFIVCMTYAFHTPDKLCFILDLMNGGDLHYHLSQHGVFSEKEMRFYATE
  IILGLEHMHNRFVVYRDLKPANILLDEHGHARISDLGLACDFSKKKPHASVGTHGYMAPE
  VLQKGTAYDSSADWFSLGCMLFKLLRGHSPFRQHKTKDKHEIDRMTLTVNVELPDTFSPE
  LKSLLEGLLQRDVSKRLGCHGGGSQEVKEHSFFKGVDWQHVYLQKYPPPLIPPRGEVNAA
  DAFDIGSFDEEDTKGIKLLDCDQELYKNFPLVISERWQQEVTETVYEAVNADTDKIEARK
  RAKNKQLGHEEDYALGKDCIMHGYMLKLGNPFLTQWQRRYFYLFPNRLEWRGEGESRQNL
  LTMEQILSVEETQIKDKKCILFRIKGGKQFVLQCESDPEFVQWKKELNETFKEAQRLLRR
  APKFLNKPRSGTVELPKPSLCHRNSNGL
• Function: Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  Endocytosis (hsa04144)
  Hedgehog sig.ling pathway (hsa04340)
  Glutamatergic sy.pse (hsa04724)
  Olfactory transduction (hsa04740)
  Morphine addiction (hsa05032)
• Reactome Pathway:
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

14 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of G protein-coupled receptor kinase 3 (GRK3).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of G protein-coupled receptor kinase 3 (GRK3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of G protein-coupled receptor kinase 3 (GRK3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of G protein-coupled receptor kinase 3 (GRK3).	[4]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of G protein-coupled receptor kinase 3 (GRK3).	[5]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of G protein-coupled receptor kinase 3 (GRK3).	[6]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of G protein-coupled receptor kinase 3 (GRK3).	[7]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of G protein-coupled receptor kinase 3 (GRK3).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol decreases the expression of G protein-coupled receptor kinase 3 (GRK3).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of G protein-coupled receptor kinase 3 (GRK3).	[10]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of G protein-coupled receptor kinase 3 (GRK3).	[11]
PMID28870136-Compound-48	DMPIM9L	Patented	PMID28870136-Compound-48 decreases the expression of G protein-coupled receptor kinase 3 (GRK3).	[6]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of G protein-coupled receptor kinase 3 (GRK3).	[13]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of G protein-coupled receptor kinase 3 (GRK3).	[14]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of G protein-coupled receptor kinase 3 (GRK3).	[12]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [3] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [4] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [5] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [6] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [7] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [8] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [9] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [10] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [11] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [12] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [13] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [14] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.