Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT05Z3MC)

• DOT Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2)
• Synonyms: G gamma-I
• Gene Name: GNG2
• Related Disease:
  Skin carcinoma
  Abdominal aortic aneurysm
  IgA nephropathy
  Multiple sclerosis
• UniProt ID: GBG2_HUMAN
• PDB ID: 4KFM ; 5HE0 ; 5HE1 ; 5HE2 ; 5HE3 ; 5UKK ; 5UKL ; 5UKM ; 5UZ7 ; 6B3J ; 6CRK ; 6D9H ; 6DDE ; 6DDF ; 6E3Y ; 6EG8 ; 6G79 ; 6GDG ; 6K41 ; 6K42 ; 6KPF ; 6KPG ; 6LFM ; 6LFO ; 6LI3 ; 6LMK ; 6LML ; 6M1H ; 6M1I ; 6M8S ; 6N4B ; 6NI3 ; 6NIY ; 6OIJ ; 6OIK ; 6OMM ; 6ORV ; 6OS9 ; 6OSA ; 6OT0 ; 6P9X ; 6P9Y ; 6PB0 ; 6PB1 ; 6PT0 ; 6UUN ; 6UUS ; 6UVA ; 6VCB ; 6VMS ; 6VN7 ; 6WHA ; 6WHC ; 6WI9 ; 6WPW ; 6WWZ ; 6WZG ; 6X18 ; 6X19 ; 6X1A ; 6XBJ ; 6XBK ; 6XBL ; 6XBM ; 6XOX ; 7AUE ; 7BB6 ; 7BB7 ; 7C2E ; 7CFM ; 7CFN ; 7CKW ; 7CKX ; 7CKY ; 7CKZ ; 7CMU ; 7CMV ; 7CRH ; 7CX2 ; 7CX3 ; 7CX4 ; 7D76 ; 7D77 ; 7D7M ; 7DFL ; 7E14 ; 7E2X ; 7E2Y ; 7E2Z ; 7E32 ; 7E33 ; 7E9G ; 7E9H ; 7EB2 ; 7EJ0 ; 7EJ8 ; 7EJA ; 7EJK ; 7EJX ; 7EO2 ; 7EO4 ; 7EPT ; 7EUO ; 7EVW ; 7EVY ; 7EVZ ; 7EW0 ; 7EW1 ; 7EW2 ; 7EW3 ; 7EW4 ; 7EW7 ; 7EXD ; 7EZH ; 7EZK ; 7EZM ; 7F0T ; 7F1O ; 7F1Q ; 7F1R ; 7F1S ; 7F1Z ; 7F23 ; 7F24 ; 7F4D ; 7F4F ; 7F4H ; 7F4I ; 7F53 ; 7F54 ; 7F55 ; 7F58 ; 7F6G ; 7F6H ; 7F6I ; 7F8V ; 7F8W ; 7F9Y ; 7F9Z ; 7JHJ ; 7JOZ ; 7JV5 ; 7JVP ; 7JVQ ; 7JVR ; 7K7L ; 7K7Z ; 7KH0 ; 7KI0 ; 7KI1 ; 7L1U ; 7L1V ; 7LCI ; 7LD3 ; 7LD4 ; 7LLL ; 7LLY ; 7MBX ; 7MBY ; 7MTS ; 7NA7 ; 7NA8 ; 7P00 ; 7P02 ; 7QVM ; 7RA3 ; 7RAN ; 7RBT ; 7RG9 ; 7RGP ; 7RKF ; 7RKM ; 7RKN ; 7RKX ; 7RKY ; 7RMG ; 7RMH ; 7RMI ; 7RTB ; 7RYC ; 7S1M ; 7S3I ; 7S8L ; 7S8M ; 7S8N ; 7S8O ; 7S8P ; 7SBF ; 7SCG ; 7SF7 ; 7SF8 ; 7SR8 ; 7SRR ; 7T10 ; 7T11 ; 7T2G ; 7T2H ; 7T6B ; 7T8X ; 7T90 ; 7T94 ; 7T96 ; 7T9I ; 7T9N ; 7TMW ; 7TRK ; 7TRP ; 7TRQ ; 7TRS ; 7TUZ ; 7TYF ; 7TYH ; 7TYI ; 7TYL ; 7TYN ; 7TYO ; 7TYW ; 7TYX ; 7TYY ; 7TZF ; 7U2K ; 7U2L ; 7UM5 ; 7UM6 ; 7UM7 ; 7UTZ ; 7V68 ; 7V69 ; 7V6A ; 7VDH ; 7VDL ; 7VDM ; 7VFX ; 7VGX ; 7VIE ; 7VIF ; 7VIG ; 7VIH ; 7VKT ; 7VL8 ; 7VL9 ; 7VLA ; 7VUG ; 7VUH ; 7VUI ; 7VUJ ; 7VUY ; 7VUZ ; 7VV3 ; 7VV5 ; 7W0L ; 7W0M ; 7W0N ; 7W0O ; 7W0P ; 7W2Z ; 7W3Z ; 7W40 ; 7W53 ; 7W55 ; 7W56 ; 7W57 ; 7W6P ; 7W7E ; 7WCM ; 7WCN ; 7WF7 ; 7WJ5 ; 7WKD ; 7WU2 ; 7WU3 ; 7WU4 ; 7WU5 ; 7WU9 ; 7WUI ; 7WUJ ; 7WUQ ; 7WV9 ; 7WVU ; 7WVV ; 7WVW ; 7WVX ; 7WVY ; 7WXU ; 7WXW ; 7WY0 ; 7WY5 ; 7WY8 ; 7WYB ; 7WZ4 ; 7WZ7 ; 7X10 ; 7X2C ; 7X2D ; 7X2F ; 7X2V ; 7X5H ; 7X8R ; 7X8S ; 7X9A ; 7X9B ; 7X9C ; 7X9Y ; 7XA3 ; 7XBD ; 7XBW ; 7XBX ; 7XJJ ; 7XJK ; 7XJL ; 7XK2 ; 7XK8 ; 7XKD ; 7XKE ; 7XKF ; 7XMR ; 7XMS ; 7XMT ; 7XOU ; 7XOV ; 7XOW ; 7XP4 ; 7XP5 ; 7XP6 ; 7XT8 ; 7XT9 ; 7XTA ; 7XTB ; 7XTC ; 7XTQ ; 7XV3 ; 7XW5 ; 7XW6 ; 7XXH ; 7XXI ; 7XY6 ; 7XY7 ; 7XZ5 ; 7XZ6 ; 7Y1F ; 7Y24 ; 7Y26 ; 7Y27 ; 7Y3G ; 7Y64 ; 7Y65 ; 7Y66 ; 7Y67 ; 7Y89 ; 7YAC ; 7YAE ; 7YDH ; 7YDJ ; 7YDM ; 7YDP ; 7YFC ; 7YFD ; 7YKD ; 7YON ; 7YOO ; 7YP7 ; 7YS6 ; 8DDW ; 8DDX ; 8DPF ; 8DPG ; 8DPH ; 8DPI ; 8DWC ; 8DWG ; 8DWH ; 8DZP ; 8DZQ ; 8DZR ; 8DZS ; 8E3X ; 8E3Y ; 8E3Z ; 8E9W ; 8E9X ; 8E9Y ; 8E9Z ; 8EFL ; 8EIT ; 8EJC ; 8EJK ; 8EMW ; 8EMX ; 8F0J ; 8F0K ; 8F2A ; 8F2B ; 8F76 ; 8FEG ; 8FLQ ; 8FLR ; 8FLS ; 8FLT ; 8FLU ; 8FMZ ; 8FN0 ; 8FN1 ; 8FU6 ; 8FX5 ; 8G05 ; 8G2Y ; 8G59 ; 8G94 ; 8GHV ; 8GUQ ; 8GUR ; 8GUS ; 8GY7 ; 8H0P ; 8H0Q ; 8H2G ; 8H4I ; 8H4K ; 8H4L ; 8H8J ; 8HBD ; 8HCQ ; 8HCX ; 8HDO ; 8HDP ; 8HIX ; 8HJ0 ; 8HJ2 ; 8HJ5 ; 8HMP ; 8HMV ; 8HNK ; 8HNL ; 8HNM ; 8HPT ; 8HQC ; 8HQE ; 8HQM ; 8HQN ; 8HS3 ; 8HSC ; 8HVI ; 8I2G ; 8I95 ; 8I97 ; 8I9A ; 8I9L ; 8I9S ; 8IA2 ; 8IA7 ; 8IA8 ; 8IBU ; 8IBV ; 8IC0 ; 8ID3 ; 8ID4 ; 8ID6 ; 8ID8 ; 8ID9 ; 8IRR ; 8IRS ; 8IRT ; 8IRU ; 8IRV ; 8ITF ; 8IUK ; 8IUL ; 8IUM ; 8IW1 ; 8IW4 ; 8IW7 ; 8IW9 ; 8IYS ; 8IZB ; 8J18 ; 8J19 ; 8J1A ; 8J6D ; 8J6P ; 8J6Q ; 8J6R ; 8JD3 ; 8JD5 ; 8JD6 ; 8JHY ; 8JII ; 8JIL ; 8JIM ; 8JKB ; 8JLJ ; 8JLK ; 8JLN ; 8JLO ; 8JLP ; 8JLQ ; 8JLR ; 8JLZ ; 8JR9 ; 8JSP ; 8JZ7 ; 8JZZ ; 8K2X ; 8K4N ; 8KGK ; 8KH4 ; 8KH5 ; 8PM2 ; 8SAI ; 8SG1 ; 8TB0 ; 8THK ; 8THL ; 8U26 ; 8U7Z ; 8U81 ; 8U82 ; 8U83 ; 8U84 ; 8W87 ; 8W88 ; 8W89 ; 8W8A ; 8W8B ; 8WPU ; 8WRB
• Pfam ID: PF00631
• Sequence:
  MASNNTASIAQARKLVEQLKMEANIDRIKVSKAAADLMAYCEAHAKEDPLLTPVPASENP
  FREKKFFCAIL
• Function: Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.
• Tissue Specificity: Expressed in fetal tissues, including testis, adrenal gland, brain, white blood cells and brain.
• KEGG Pathway:
  Ras sig.ling pathway (hsa04014)
  Chemokine sig.ling pathway (hsa04062)
  PI3K-Akt sig.ling pathway (hsa04151)
  Apelin sig.ling pathway (hsa04371)
  Circadian entrainment (hsa04713)
  Retrograde endocan.binoid sig.ling (hsa04723)
  Glutamatergic sy.pse (hsa04724)
  Cholinergic sy.pse (hsa04725)
  Serotonergic sy.pse (hsa04726)
  GABAergic sy.pse (hsa04727)
  Dopaminergic sy.pse (hsa04728)
  Relaxin sig.ling pathway (hsa04926)
  Morphine addiction (hsa05032)
  Alcoholism (hsa05034)
  Human cytomegalovirus infection (hsa05163)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Human immunodeficiency virus 1 infection (hsa05170)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  Glucagon signaling in metabolic regulation (R-HSA-163359)
  G-protein activation (R-HSA-202040)
  Glucagon-like Peptide-1 (GLP1) regulates insulin secretion (R-HSA-381676)
  ADP signalling through P2Y purinoceptor 12 (R-HSA-392170)
  G beta (R-HSA-392451)
  Prostacyclin signalling through prostacyclin receptor (R-HSA-392851)
  Adrenaline,noradrenaline inhibits insulin secretion (R-HSA-400042)
  Ca2+ pathway (R-HSA-4086398)
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (12/13) signalling events (R-HSA-416482)
  G beta (R-HSA-418217)
  G alpha (s) signalling events (R-HSA-418555)
  ADP signalling through P2Y purinoceptor 1 (R-HSA-418592)
  G alpha (i) signalling events (R-HSA-418594)
  G alpha (z) signalling events (R-HSA-418597)
  Glucagon-type ligand receptors (R-HSA-420092)
  Thromboxane signalling through TP receptor (R-HSA-428930)
  Vasopressin regulates renal water homeostasis via Aquaporins (R-HSA-432040)
  Thrombin signalling through proteinase activated receptors (PARs) (R-HSA-456926)
  Presynaptic function of Kainate receptors (R-HSA-500657)
  Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding (R-HSA-6814122)
  G beta (R-HSA-8964315)
  G beta (R-HSA-8964616)
  Extra-nuclear estrogen signaling (R-HSA-9009391)
  GPER1 signaling (R-HSA-9634597)
  ADORA2B mediated anti-inflammatory cytokines production (R-HSA-9660821)
  Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits (R-HSA-997272)
  Activation of G protein gated Potassium channels (R-HSA-1296041)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Skin carcinoma	DISUZREN	Definitive	Genetic Variation	[1]
Abdominal aortic aneurysm	DISD06OF	Strong	Biomarker	[2]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[3]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2).	[14]

9 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 Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2).	[8]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2).	[9]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2).	[12]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 (GNG2).	[15]

References

• [1] Genome-wide association studies identify several new loci associated with pigmentation traits and skin cancer risk in European Americans.Hum Mol Genet. 2013 Jul 15;22(14):2948-59. doi: 10.1093/hmg/ddt142. Epub 2013 Apr 1.
• [2] miR-30a-GNG2 and miR-15b-ACSS2 Interaction Pairs May Be Potentially Crucial for Development of Abdominal Aortic Aneurysm by Influencing Inflammation.DNA Cell Biol. 2019 Dec;38(12):1540-1556. doi: 10.1089/dna.2019.4994. Epub 2019 Nov 15.
• [3] 3'UTR variants of TNS3, PHLDB1, NTN4, and GNG2 genes are associated with IgA nephropathy risk in Chinese Han population.Int Immunopharmacol. 2019 Jun;71:295-300. doi: 10.1016/j.intimp.2019.03.041. Epub 2019 Mar 28.
• [4] Correlation between LincR-Gng2-5'and LincR-Epas1-3'as with the severity of multiple sclerosis in Egyptian patients.Int J Neurosci. 2020 May;130(5):515-521. doi: 10.1080/00207454.2019.1695610. Epub 2019 Dec 2.
• [5] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [6] 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.
• [7] 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.
• [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] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [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] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [13] Endoplasmic reticulum stress impairs insulin signaling through mitochondrial damage in SH-SY5Y cells. Neurosignals. 2012;20(4):265-80.
• [14] 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.
• [15] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.