Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUU8V2S)

• DOT Name: G protein-coupled receptor kinase 4 (GRK4)
• Synonyms: EC 2.7.11.16; G protein-coupled receptor kinase GRK4; ITI1
• Gene Name: GRK4
• Related Disease:
  Essential hypertension
  Breast cancer
  Breast carcinoma
  Diabetic kidney disease
  High blood pressure
  Huntington disease
  Obesity
  Venous thromboembolism
  Coronary atherosclerosis
  Coronary heart disease
  Myocardial infarction
• UniProt ID: GRK4_HUMAN
• PDB ID: 4YHJ
• EC Number: 2.7.11.16
• Pfam ID: PF00069 ; PF00615
• Sequence:
  MELENIVANSLLLKARQGGYGKKSGRSKKWKEILTLPPVSQCSELRHSIEKDYSSLCDKQ
  PIGRRLFRQFCDTKPTLKRHIEFLDAVAEYEVADDEDRSDCGLSILDRFFNDKLAAPLPE
  IPPDVVTECRLGLKEENPSKKAFEECTRVAHNYLRGEPFEEYQESSYFSQFLQWKWLERQ
  PVTKNTFRHYRVLGKGGFGEVCACQVRATGKMYACKKLQKKRIKKRKGEAMALNEKRILE
  KVQSRFVVSLAYAYETKDALCLVLTIMNGGDLKFHIYNLGNPGFDEQRAVFYAAELCCGL
  EDLQRERIVYRDLKPENILLDDRGHIRISDLGLATEIPEGQRVRGRVGTVGYMAPEVVNN
  EKYTFSPDWWGLGCLIYEMIQGHSPFKKYKEKVKWEEVDQRIKNDTEEYSEKFSEDAKSI
  CRMLLTKNPSKRLGCRGEGAAGVKQHPVFKDINFRRLEANMLEPPFCPDPHAVYCKDVLD
  IEQFSVVKGIYLDTADEDFYARFATGCVSIPWQNEMIESGCFKDINKSESEEALPLDLDK
  NIHTPVSRPNRGFFYRLFRRGGCLTMVPSEKEVEPKQC
• Function: Specifically phosphorylates the activated forms of G protein-coupled receptors. GRK4-alpha can phosphorylate rhodopsin and its activity is inhibited by calmodulin; the other three isoforms do not phosphorylate rhodopsin and do not interact with calmodulin. GRK4-alpha and GRK4-gamma phosphorylate DRD3. Phosphorylates ADRB2.
• Tissue Specificity: Isoform 1, isoform 2, isoform 3, and isoform 4 are expressed in testis. Isoform 4 is expressed in myometrium.
• KEGG Pathway:
  Chemokine sig.ling pathway (hsa04062)
  Endocytosis (hsa04144)
  Morphine addiction (hsa05032)

Molecular Interaction Atlas (MIA) of This DOT

11 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Essential hypertension	DIS7WI98	Definitive	Genetic Variation	[1]
Breast cancer	DIS7DPX1	Strong	Biomarker	[2]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[2]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[3]
High blood pressure	DISY2OHH	Strong	Biomarker	[4]
Huntington disease	DISQPLA4	Strong	Genetic Variation	[5]
Obesity	DIS47Y1K	Strong	Genetic Variation	[6]
Venous thromboembolism	DISUR7CR	Strong	Genetic Variation	[7]
Coronary atherosclerosis	DISKNDYU	Limited	Genetic Variation	[8]
Coronary heart disease	DIS5OIP1	Limited	Genetic Variation	[8]
Myocardial infarction	DIS655KI	Limited	Genetic Variation	[8]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Metoprolol	DMOJ0V6	Approved	G protein-coupled receptor kinase 4 (GRK4) affects the response to substance of Metoprolol.	[15]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of G protein-coupled receptor kinase 4 (GRK4).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of G protein-coupled receptor kinase 4 (GRK4).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of G protein-coupled receptor kinase 4 (GRK4).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of G protein-coupled receptor kinase 4 (GRK4).	[12]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of G protein-coupled receptor kinase 4 (GRK4).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of G protein-coupled receptor kinase 4 (GRK4).	[13]

References

• [1] Common variants of the G protein-coupled receptor type 4 are associated with human essential hypertension and predict the blood pressure response to angiotensin receptor blockade.Pharmacogenomics J. 2016 Feb;16(1):3-9. doi: 10.1038/tpj.2015.6. Epub 2015 Mar 3.
• [2] Expression of G protein-coupled receptor kinase 4 is associated with breast cancer tumourigenesis.J Pathol. 2008 Nov;216(3):317-27. doi: 10.1002/path.2414.
• [3] Renoprotective effects of berberine and its possible molecular mechanisms in combination of high-fat diet and low-dose streptozotocin-induced diabetic rats.Mol Biol Rep. 2013 Mar;40(3):2405-18. doi: 10.1007/s11033-012-2321-5. Epub 2012 Nov 30.
• [4] In-utero cold stress causes elevation of blood pressure via impaired vascular dopamine D(1) receptor in offspring.Clin Exp Hypertens. 2020;42(2):99-104. doi: 10.1080/10641963.2019.1571603. Epub 2019 Jan 30.
• [5] Common SNP-based haplotype analysis of the 4p16.3 Huntington disease gene region.Am J Hum Genet. 2012 Mar 9;90(3):434-44. doi: 10.1016/j.ajhg.2012.01.005. Epub 2012 Mar 1.
• [6] Gender-based differences on the association between salt-sensitive genes and obesity in Korean children aged between 8 and 9 years.PLoS One. 2015 Mar 13;10(3):e0120111. doi: 10.1371/journal.pone.0120111. eCollection 2015.
• [7] Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism.Blood. 2019 Nov 7;134(19):1645-1657. doi: 10.1182/blood.2019000435.
• [8] G protein receptor kinase 4 polymorphisms: -blocker pharmacogenetics and treatment-related outcomes in hypertension.Hypertension. 2012 Oct;60(4):957-64. doi: 10.1161/HYPERTENSIONAHA.112.198721. Epub 2012 Sep 4.
• [9] Valproic acid promotes mitochondrial dysfunction in primary human hepatocytes in vitro; impact of C/EBP-controlled gene expression. Arch Toxicol. 2020 Oct;94(10):3463-3473. doi: 10.1007/s00204-020-02835-x. Epub 2020 Jul 4.
• [10] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [11] Arsenic suppresses gene expression in promyelocytic leukemia cells partly through Sp1 oxidation. Blood. 2005 Jul 1;106(1):304-10.
• [12] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [13] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [14] 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.
• [15] G-protein-coupled receptor kinase 4 polymorphisms and blood pressure response to metoprolol among African Americans: sex-specificity and interactions. Am J Hypertens. 2009 Mar;22(3):332-8. doi: 10.1038/ajh.2008.341. Epub 2009 Jan 1.