Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT9G194Y)

DOT Name Oxysterol-binding protein-related protein 3 (OSBPL3)
Synonyms ORP-3; OSBP-related protein 3
Gene Name OSBPL3
Related Disease
Advanced cancer ( )
B-cell neoplasm ( )
Non-alcoholic fatty liver disease ( )
Non-insulin dependent diabetes ( )
Amyotrophic lateral sclerosis ( )
Crohn disease ( )
UniProt ID
OSBL3_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
7CYZ; 7DEI; 7DEJ
Pfam ID
PF01237 ; PF15409
Sequence
MMSDEKNLGVSQKLVSPSRSTSSCSSKQGSRQDSWEVVEGLRGEMNYTQEPPVQKGFLLK
KRKWPLKGWHKRFFYLDKGILKYAKSQTDIEREKLHGCIDVGLSVMSVKKSSKCIDLDTE
EHIYHLKVKSEEVFDEWVSKLRHHRMYRQNEIAMFPHEVNHFFSGSTITDSSSGVFDSIS
SRKRSSISKQNLFQTGSNVSFSCGGETRVPLWLQSSEDMEKCSKDLAHCHAYLVEMSQLL
QSMDVLHRTYSAPAINAIQGGSFESPKKEKRSHRRWRSRAIGKDAKGTLQVPKPFSGPVR
LHSSNPNLSTLDFGEEKNYSDGSETSSEFSKMQEDLCHIAHKVYFTLRSAFNIMSAEREK
LKQLMEQDASSSPSAQVIGLKNALSSALAQNTDLKERLRRIHAESLLLDSPAVAKSGDNL
AEENSRDENRALVHQLSNESRLSITDSLSEFFDAQEVLLSPSSSENEISDDDSYVSDISD
NLSLDNLSNDLDNERQTLGPVLDSGREAKSRRRTCLPAPCPSSSNISLWNILRNNIGKDL
SKVAMPVELNEPLNTLQRLCEELEYSELLDKAAQIPSPLERMVYVAAFAISAYASSYYRA
GSKPFNPVLGETYECIREDKGFQFFSEQVSHHPPISACHAESRNFVFWQDVRWKNKFWGK
SMEIVPIGTTHVTLPVFGDHFEWNKVTSCIHNILSGQRWIEHYGEIVIKNLHDDSCYCKV
NFIKAKYWSTNAHEIEGTVFDRSGKAVHRLFGKWHESIYCGGGSSSACVWRANPMPKGYE
QYYSFTQFALELNEMDPSSKSLLPPTDTRFRPDQRFLEEGNLEEAEIQKQRIEQLQRERR
RVLEENHVEHQPRFFRKSDDDSWVSNGTYLELRKDLGFSKLDHPVLW
Function
Phosphoinositide-binding protein which associates with both cell and endoplasmic reticulum (ER) membranes. Can bind to the ER membrane protein VAPA and recruit VAPA to plasma membrane sites, thus linking these intracellular compartments. The ORP3-VAPA complex stimulates RRAS signaling which in turn attenuates integrin beta-1 (ITGB1) activation at the cell surface. With VAPA, may regulate ER morphology. Has a role in regulation of the actin cytoskeleton, cell polarity and cell adhesion. Binds to phosphoinositides with preference for PI(3,4)P2 and PI(3,4,5)P3. Also binds 25-hydroxycholesterol and cholesterol.
Tissue Specificity
Expressed in a subset of small lymphocytes (at protein level). Expressed at high concentration in kidney, lymph node and thymus. Expressed at moderate concentration in stomach, jejunum, ileum, appendix, spleen, leukocytes, trachea, lung and thyroid gland. Expressed at low concentration in whole brain, esophagus, duodenum, ileocecum, colon, skeletal muscle, bone marrow, placenta and mammary gland . Isoform 1a, isoform 1b, isoform 1c and isoform 1d are highly expressed in brain, bone marrow, colon, kidney, lung, skeletal muscle, spleen, thymus and thyroid. Not expressed in heart and liver. Isoform 2a, isoform 2b, isoform 2c and isoform 2d are expressed in brain, bone marrow, kidney, skeletal muscle, spleen, thymus and thyroid. Not expressed in heart, liver and lung .
Reactome Pathway
Synthesis of bile acids and bile salts (R-HSA-192105 )

Molecular Interaction Atlas (MIA) of This DOT

6 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Advanced cancer DISAT1Z9 Strong Genetic Variation [1]
B-cell neoplasm DISVY326 Strong Biomarker [1]
Non-alcoholic fatty liver disease DISDG1NL Strong Altered Expression [2]
Non-insulin dependent diabetes DISK1O5Z Strong Genetic Variation [3]
Amyotrophic lateral sclerosis DISF7HVM Limited Biomarker [4]
Crohn disease DIS2C5Q8 Limited Genetic Variation [5]
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⏷ Show the Full List of 6 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas 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 increases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [6]
Ciclosporin DMAZJFX Approved Ciclosporin decreases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [7]
Tretinoin DM49DUI Approved Tretinoin decreases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [8]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [9]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [10]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [11]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [12]
Quercetin DM3NC4M Approved Quercetin increases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [13]
Vorinostat DMWMPD4 Approved Vorinostat increases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [14]
Triclosan DMZUR4N Approved Triclosan decreases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [15]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene decreases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [16]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [17]
Bisphenol A DM2ZLD7 Investigative Bisphenol A decreases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [19]
Formaldehyde DM7Q6M0 Investigative Formaldehyde increases the expression of Oxysterol-binding protein-related protein 3 (OSBPL3). [20]
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⏷ Show the Full List of 14 Drug(s)
1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
PMID28870136-Compound-52 DMFDERP Patented PMID28870136-Compound-52 affects the phosphorylation of Oxysterol-binding protein-related protein 3 (OSBPL3). [18]
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References

1 Aneuploidy-inducing gene knockdowns overlap with cancer mutations and identify Orp3 as a B-cell lymphoma suppressor.Oncogene. 2020 Feb;39(7):1445-1465. doi: 10.1038/s41388-019-1073-2. Epub 2019 Oct 28.
2 Impaired SUMOylation of nuclear receptor LRH-1 promotes nonalcoholic fatty liver disease.J Clin Invest. 2017 Feb 1;127(2):583-592. doi: 10.1172/JCI85499. Epub 2017 Jan 17.
3 Genome-wide association study of coronary artery calcified atherosclerotic plaque in African Americans with type 2 diabetes.BMC Genet. 2017 Dec 8;18(1):105. doi: 10.1186/s12863-017-0572-9.
4 Oxysterol-binding protein ORP3 rescues the Amyotrophic Lateral Sclerosis-linked mutant VAPB phenotype.Exp Cell Res. 2016 Feb 1;341(1):18-31. doi: 10.1016/j.yexcr.2016.01.013. Epub 2016 Jan 23.
5 Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci.Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14747-52. doi: 10.1073/pnas.0706645104. Epub 2007 Sep 5.
6 The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
7 Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
8 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.
9 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.
10 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.
11 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
12 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.
13 Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
14 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.
15 Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
16 Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
17 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.
18 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.
19 Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.
20 Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.