Details of Drug Off-Target (DOT)

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

• DOT Name: BOS complex subunit NCLN (NCLN)
• Synonyms: Nicalin; Nicastrin-like protein
• Gene Name: NCLN
• Related Disease: Ovarian neoplasm
• UniProt ID: NCLN_HUMAN
• PDB ID: 6W6L
• Pfam ID: PF04389
• Sequence:
  MLEEAGEVLENMLKASCLPLGFIVFLPAVLLLVAPPLPAADAAHEFTVYRMQQYDLQGQP
  YGTRNAVLNTEARTMAAEVLSRRCVLMRLLDFSYEQYQKALRQSAGAVVIILPRAMAAVP
  QDVVRQFMEIEPEMLAMETAVPVYFAVEDEALLSIYKQTQAASASQGSASAAEVLLRTAT
  ANGFQMVTSGVQSKAVSDWLIASVEGRLTGLGGEDLPTIVIVAHYDAFGVAPWLSLGADS
  NGSGVSVLLELARLFSRLYTYKRTHAAYNLLFFASGGGKFNYQGTKRWLEDNLDHTDSSL
  LQDNVAFVLCLDTVGRGSSLHLHVSKPPREGTLQHAFLRELETVAAHQFPEVRFSMVHKR
  INLAEDVLAWEHERFAIRRLPAFTLSHLESHRDGQRSSIMDVRSRVDSKTLTRNTRIIAE
  ALTRVIYNLTEKGTPPDMPVFTEQMQIQQEQLDSVMDWLTNQPRAAQLVDKDSTFLSTLE
  HHLSRYLKDVKQHHVKADKRDPEFVFYDQLKQVMNAYRVKPAVFDLLLAVGIAAYLGMAY
  VAVQHFSLLYKTVQRLLVKAKTQ
• Function: Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes. The MPT complex takes over after the SEC61 complex: following membrane insertion of the first few transmembrane segments of proteins by the SEC61 complex, the MPT complex occludes the lateral gate of the SEC61 complex to promote insertion of subsequent transmembrane regions. May antagonize Nodal signaling and subsequent organization of axial structures during mesodermal patterning, via its interaction with NOMO.
• Tissue Specificity: Highly expressed in pancreas and skeletal muscle and, at lower levels, in heart.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ovarian neoplasm	DISEAFTY	Strong	Genetic Variation	[1]

10 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 BOS complex subunit NCLN (NCLN).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of BOS complex subunit NCLN (NCLN).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of BOS complex subunit NCLN (NCLN).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of BOS complex subunit NCLN (NCLN).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of BOS complex subunit NCLN (NCLN).	[6]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of BOS complex subunit NCLN (NCLN).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of BOS complex subunit NCLN (NCLN).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of BOS complex subunit NCLN (NCLN).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of BOS complex subunit NCLN (NCLN).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of BOS complex subunit NCLN (NCLN).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of BOS complex subunit NCLN (NCLN).	[9]

References

• [1] Genome-wide association studies identify susceptibility loci for epithelial ovarian cancer in east Asian women.Gynecol Oncol. 2019 May;153(2):343-355. doi: 10.1016/j.ygyno.2019.02.023. Epub 2019 Mar 19.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [5] 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.
• [6] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [7] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [8] 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.
• [9] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [10] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [11] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [12] 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.