Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ8KDFX)

• DOT Name: ATPase GET3 (GET3)
• Synonyms: EC 3.6.-.-; Arsenical pump-driving ATPase; Arsenite-stimulated ATPase; Guided entry of tail-anchored proteins factor 3, ATPase; Transmembrane domain recognition complex 40 kDa ATPase subunit; hARSA-I; hASNA-I
• Gene Name: GET3
• Related Disease: Parkinson disease
• UniProt ID: GET3_HUMAN
• PDB ID: 6SO5; 8CQZ; 8CR1; 8CR2
• EC Number: 3.6.-.-
• Pfam ID: PF02374
• Sequence:
  MAAGVAGWGVEAEEFEDAPDVEPLEPTLSNIIEQRSLKWIFVGGKGGVGKTTCSCSLAVQ
  LSKGRESVLIISTDPAHNISDAFDQKFSKVPTKVKGYDNLFAMEIDPSLGVAELPDEFFE
  EDNMLSMGKKMMQEAMSAFPGIDEAMSYAEVMRLVKGMNFSVVVFDTAPTGHTLRLLNFP
  TIVERGLGRLMQIKNQISPFISQMCNMLGLGDMNADQLASKLEETLPVIRSVSEQFKDPE
  QTTFICVCIAEFLSLYETERLIQELAKCKIDTHNIIVNQLVFPDPEKPCKMCEARHKIQA
  KYLDQMEDLYEDFHIVKLPLLPHEVRGADKVNTFSALLLEPYKPPSAQ
• Function: ATPase required for the post-translational delivery of tail-anchored (TA) proteins to the endoplasmic reticulum. Recognizes and selectively binds the transmembrane domain of TA proteins in the cytosol. This complex then targets to the endoplasmic reticulum by membrane-bound receptors GET1/WRB and CAMLG/GET2, where the tail-anchored protein is released for insertion. This process is regulated by ATP binding and hydrolysis. ATP binding drives the homodimer towards the closed dimer state, facilitating recognition of newly synthesized TA membrane proteins. ATP hydrolysis is required for insertion. Subsequently, the homodimer reverts towards the open dimer state, lowering its affinity for the GET1-CAMLG receptor, and returning it to the cytosol to initiate a new round of targeting. May be involved in insulin signaling.
• Tissue Specificity: Expressed in the epithelial cells of the liver, kidney, and stomach wall, in the adrenal medulla, in the islet cells of the pancreas, in the red pulp of the spleen, and in cardiac and skeletal muscle.
• KEGG Pathway: Protein export (hsa03060)
• Reactome Pathway: Insertion of tail-anchored proteins into the endoplasmic reticulum membrane (R-HSA-9609523)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Parkinson disease	DISQVHKL	Limited	Biomarker	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	ATPase GET3 (GET3) affects the response to substance of Cisplatin.	[9]

6 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 ATPase GET3 (GET3).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of ATPase GET3 (GET3).	[3]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATPase GET3 (GET3).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of ATPase GET3 (GET3).	[5]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of ATPase GET3 (GET3).	[6]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of ATPase GET3 (GET3).	[8]

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 affects the methylation of ATPase GET3 (GET3).	[7]

References

• [1] A systematic screening to identify de novo mutations causing sporadic early-onset Parkinson's disease.Hum Mol Genet. 2015 Dec 1;24(23):6711-20. doi: 10.1093/hmg/ddv376. Epub 2015 Sep 11.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Retinoic acid-induced downmodulation of telomerase activity in human cancer cells. Exp Mol Pathol. 2005 Oct;79(2):108-17.
• [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] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [6] Differential expression and response to arsenic stress of MRPs and ASAN1 determine sensitivity of classical multidrug-resistant leukemia cells to arsenic trioxide. Leuk Res. 2016 Nov;50:116-122. doi: 10.1016/j.leukres.2016.10.003. Epub 2016 Oct 3.
• [7] 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.
• [8] Low-dose Bisphenol A exposure alters the functionality and cellular environment in a human cardiomyocyte model. Environ Pollut. 2023 Oct 15;335:122359. doi: 10.1016/j.envpol.2023.122359. Epub 2023 Aug 9.
• [9] ASNA-1 activity modulates sensitivity to cisplatin. Cancer Res. 2010 Dec 15;70(24):10321-8. doi: 10.1158/0008-5472.CAN-10-1548. Epub 2010 Oct 21.