Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7CJLY8)

• DOT Name: Ras GTPase-activating protein-binding protein 1 (G3BP1)
• Synonyms: G3BP-1; EC 3.6.4.12; EC 3.6.4.13; ATP-dependent DNA helicase VIII; hDH VIII; GAP SH3 domain-binding protein 1
• Gene Name: G3BP1
• UniProt ID: G3BP1_HUMAN
• PDB ID: 3Q90; 4FCJ; 4FCM; 4IIA; 5FW5; 6TA7; 7S17; 7SUO; 7XHF; 7XHG
• EC Number: 3.6.4.12; 3.6.4.13
• Pfam ID: PF02136 ; PF00076
• Sequence:
  MVMEKPSPLLVGREFVRQYYTLLNQAPDMLHRFYGKNSSYVHGGLDSNGKPADAVYGQKE
  IHRKVMSQNFTNCHTKIRHVDAHATLNDGVVVQVMGLLSNNNQALRRFMQTFVLAPEGSV
  ANKFYVHNDIFRYQDEVFGGFVTEPQEESEEEVEEPEERQQTPEVVPDDSGTFYDQAVVS
  NDMEEHLEEPVAEPEPDPEPEPEQEPVSEIQEEKPEPVLEETAPEDAQKSSSPAPADIAQ
  TVQEDLRTFSWASVTSKNLPPSGAVPVTGIPPHVVKVPASQPRPESKPESQIPPQRPQRD
  QRVREQRINIPPQRGPRPIREAGEQGDIEPRRMVRHPDSHQLFIGNLPHEVDKSELKDFF
  QSYGNVVELRINSGGKLPNFGFVVFDDSEPVQKVLSNRPIMFRGEVRLNVEEKKTRAARE
  GDRRDNRLRGPGGPRGGLGGGMRGPPRGGMVQKPGFGVGRGLAPRQ
• Function: Protein involved in various processes, such as stress granule formation and innate immunity. Plays an essential role in stress granule formation. Stress granules are membraneless compartments that store mRNAs and proteins, such as stalled translation pre-initiation complexes, in response to stress. Promotes formation of stress granules phase-separated membraneless compartment by undergoing liquid-liquid phase separation (LLPS) upon unfolded RNA-binding: functions as a molecular switch that triggers RNA-dependent LLPS in response to a rise in intracellular free RNA concentrations. Also acts as an ATP- and magnesium-dependent helicase: unwinds DNA/DNA, RNA/DNA, and RNA/RNA substrates with comparable efficiency. Acts unidirectionally by moving in the 5' to 3' direction along the bound single-stranded DNA. Unwinds preferentially partial DNA and RNA duplexes having a 17 bp annealed portion and either a hanging 3' tail or hanging tails at both 5'- and 3'-ends. Plays an essential role in innate immunity by promoting CGAS and RIGI activity. Participates in the DNA-triggered cGAS/STING pathway by promoting the DNA binding and activation of CGAS. Triggers the condensation of cGAS, a process probably linked to the formation of membrane-less organelles. Enhances also RIGI-induced type I interferon production probably by helping RIGI at sensing pathogenic RNA. May also act as a phosphorylation-dependent sequence-specific endoribonuclease in vitro: Cleaves exclusively between cytosine and adenine and cleaves MYC mRNA preferentially at the 3'-UTR.
• Tissue Specificity: Ubiquitous.
• KEGG Pathway: Cytosolic D.-sensing pathway (hsa04623)
• Reactome Pathway: SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Regulation of Drug Effects of 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Milchsaure	DM462BT	Investigative	Ras GTPase-activating protein-binding protein 1 (G3BP1) increases the abundance of Milchsaure.	[7]
D-glucose	DMMG2TO	Investigative	Ras GTPase-activating protein-binding protein 1 (G3BP1) increases the uptake of D-glucose.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[4]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[8]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[9]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[10]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[11]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[14]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[15]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[16]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[17]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the phosphorylation of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[5]
G1	DMTV42K	Phase 1/2	G1 increases the phosphorylation of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[12]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[13]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the phosphorylation of Ras GTPase-activating protein-binding protein 1 (G3BP1).	[18]

References

• [1] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [2] 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.
• [3] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] The G Protein-Coupled Estrogen Receptor Agonist G-1 Inhibits Nuclear Estrogen Receptor Activity and Stimulates Novel Phosphoproteomic Signatures. Toxicol Sci. 2016 Jun;151(2):434-46. doi: 10.1093/toxsci/kfw057. Epub 2016 Mar 29.
• [6] 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.
• [7] Quercetin acts via the G3BP1/YWHAZ axis to inhibit glycolysis and proliferation in oral squamous cell carcinoma. Toxicol Mech Methods. 2023 Feb;33(2):141-150. doi: 10.1080/15376516.2022.2103480. Epub 2022 Aug 9.
• [8] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [9] Minimal peroxide exposure of neuronal cells induces multifaceted adaptive responses. PLoS One. 2010 Dec 17;5(12):e14352. doi: 10.1371/journal.pone.0014352.
• [10] 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.
• [11] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [12] 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.
• [13] 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.
• [14] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [15] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [16] 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.
• [17] 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.
• [18] Functional lipidomics: Palmitic acid impairs hepatocellular carcinoma development by modulating membrane fluidity and glucose metabolism. Hepatology. 2017 Aug;66(2):432-448. doi: 10.1002/hep.29033. Epub 2017 Jun 16.