Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT34KKWK)

• DOT Name: Beta-adrenergic receptor kinase 1 (GRK2)
• Synonyms: Beta-ARK-1; EC 2.7.11.15; G-protein coupled receptor kinase 2
• Gene Name: GRK2
• UniProt ID: ARBK1_HUMAN
• PDB ID: 1BAK; 3CIK; 3KRW; 3KRX; 3V5W; 4MK0; 4PNK; 5HE1; 5UKK; 5UKL; 5UUU; 5UVC; 5WG3; 5WG4; 5WG5; 6C2Y; 6U7C; 7K7L; 7K7Z; 7PWD
• EC Number: 2.7.11.15
• Pfam ID: PF00169 ; PF00069 ; PF00615
• Sequence:
  MADLEAVLADVSYLMAMEKSKATPAARASKKILLPEPSIRSVMQKYLEDRGEVTFEKIFS
  QKLGYLLFRDFCLNHLEEARPLVEFYEEIKKYEKLETEEERVARSREIFDSYIMKELLAC
  SHPFSKSATEHVQGHLGKKQVPPDLFQPYIEEICQNLRGDVFQKFIESDKFTRFCQWKNV
  ELNIHLTMNDFSVHRIIGRGGFGEVYGCRKADTGKMYAMKCLDKKRIKMKQGETLALNER
  IMLSLVSTGDCPFIVCMSYAFHTPDKLSFILDLMNGGDLHYHLSQHGVFSEADMRFYAAE
  IILGLEHMHNRFVVYRDLKPANILLDEHGHVRISDLGLACDFSKKKPHASVGTHGYMAPE
  VLQKGVAYDSSADWFSLGCMLFKLLRGHSPFRQHKTKDKHEIDRMTLTMAVELPDSFSPE
  LRSLLEGLLQRDVNRRLGCLGRGAQEVKESPFFRSLDWQMVFLQKYPPPLIPPRGEVNAA
  DAFDIGSFDEEDTKGIKLLDSDQELYRNFPLTISERWQQEVAETVFDTINAETDRLEARK
  KAKNKQLGHEEDYALGKDCIMHGYMSKMGNPFLTQWQRRYFYLFPNRLEWRGEGEAPQSL
  LTMEEIQSVEETQIKERKCLLLKIRGGKQFILQCDSDPELVQWKKELRDAYREAQQLVQR
  VPKMKNKPRSPVVELSKVPLVQRGSANGL
• Function: Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. Key regulator of LPAR1 signaling. Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. Desensitizes LPAR1 and LPAR2 in a phosphorylation-independent manner. Positively regulates ciliary smoothened (SMO)-dependent Hedgehog (Hh) signaling pathway by facilitating the trafficking of SMO into the cilium and the stimulation of SMO activity. Inhibits relaxation of airway smooth muscle in response to blue light.
• Tissue Specificity: Expressed in peripheral blood leukocytes.
• 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:
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (s) signalling events (R-HSA-418555)
  Activation of SMO (R-HSA-5635838)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Calmodulin induced events (R-HSA-111933)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Beta-adrenergic receptor kinase 1 (GRK2).	[1]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Beta-adrenergic receptor kinase 1 (GRK2).	[2]
Isoproterenol	DMK7MEY	Approved	Isoproterenol increases the expression of Beta-adrenergic receptor kinase 1 (GRK2).	[3]
Propranolol	DM79NTF	Approved	Propranolol decreases the expression of Beta-adrenergic receptor kinase 1 (GRK2).	[3]

3 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 affects the methylation of Beta-adrenergic receptor kinase 1 (GRK2).	[4]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Beta-adrenergic receptor kinase 1 (GRK2).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Beta-adrenergic receptor kinase 1 (GRK2).	[6]

References

• [1] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [2] 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.
• [3] Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by beta-adrenergic receptor stimulation and blockade. Circulation. 1998 Oct 27;98(17):1783-9. doi: 10.1161/01.cir.98.17.1783.
• [4] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [5] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [6] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.