Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTJFGE9S)

• DOT Name: Metabotropic glutamate receptor 3 (GRM3)
• Synonyms: mGluR3
• Gene Name: GRM3
• UniProt ID: GRM3_HUMAN
• PDB ID: 3SM9; 4XAR; 5CNK; 5CNM; 6B7H; 7WI6; 7WI8; 7WIH; 8JCU; 8JCV; 8JCW; 8JCX; 8JCY; 8JCZ; 8JD0; 8JD1; 8JD2; 8JD3
• Pfam ID: PF00003 ; PF01094 ; PF07562
• Sequence:
  MKMLTRLQVLTLALFSKGFLLSLGDHNFLRREIKIEGDLVLGGLFPINEKGTGTEECGRI
  NEDRGIQRLEAMLFAIDEINKDDYLLPGVKLGVHILDTCSRDTYALEQSLEFVRASLTKV
  DEAEYMCPDGSYAIQENIPLLIAGVIGGSYSSVSIQVANLLRLFQIPQISYASTSAKLSD
  KSRYDYFARTVPPDFYQAKAMAEILRFFNWTYVSTVASEGDYGETGIEAFEQEARLRNIC
  IATAEKVGRSNIRKSYDSVIRELLQKPNARVVVLFMRSDDSRELIAAASRANASFTWVAS
  DGWGAQESIIKGSEHVAYGAITLELASQPVRQFDRYFQSLNPYNNHRNPWFRDFWEQKFQ
  CSLQNKRNHRRVCDKHLAIDSSNYEQESKIMFVVNAVYAMAHALHKMQRTLCPNTTKLCD
  AMKILDGKKLYKDYLLKINFTAPFNPNKDADSIVKFDTFGDGMGRYNVFNFQNVGGKYSY
  LKVGHWAETLSLDVNSIHWSRNSVPTSQCSDPCAPNEMKNMQPGDVCCWICIPCEPYEYL
  ADEFTCMDCGSGQWPTADLTGCYDLPEDYIRWEDAWAIGPVTIACLGFMCTCMVVTVFIK
  HNNTPLVKASGRELCYILLFGVGLSYCMTFFFIAKPSPVICALRRLGLGSSFAICYSALL
  TKTNCIARIFDGVKNGAQRPKFISPSSQVFICLGLILVQIVMVSVWLILEAPGTRRYTLA
  EKRETVILKCNVKDSSMLISLTYDVILVILCTVYAFKTRKCPENFNEAKFIGFTMYTTCI
  IWLAFLPIFYVTSSDYRVQTTTMCISVSLSGFVVLGCLFAPKVHIILFQPQKNVVTHRLH
  LNRFSVSGTGTTYSQSSASTYVPTVCNGREVLDSTTSSL
• Function: G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling inhibits adenylate cyclase activity.
• Tissue Specificity: Detected in brain cortex, thalamus, subthalamic nucleus, substantia nigra, hypothalamus, hippocampus, corpus callosum, caudate nucleus and amygdala.
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  Neuroactive ligand-receptor interaction (hsa04080)
  Glutamatergic sy.pse (hsa04724)
  Cocaine addiction (hsa05030)
• Reactome Pathway:
  Class C/3 (Metabotropic glutamate/pheromone receptors) (R-HSA-420499)
  G alpha (i) signalling events (R-HSA-418594)

Molecular Interaction Atlas (MIA) of This DOT

9 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 Metabotropic glutamate receptor 3 (GRM3).	[1]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Metabotropic glutamate receptor 3 (GRM3).	[2]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Metabotropic glutamate receptor 3 (GRM3).	[1]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Metabotropic glutamate receptor 3 (GRM3).	[3]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Metabotropic glutamate receptor 3 (GRM3).	[1]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Metabotropic glutamate receptor 3 (GRM3).	[4]
Fenofibrate	DMFKXDY	Approved	Fenofibrate increases the expression of Metabotropic glutamate receptor 3 (GRM3).	[4]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Metabotropic glutamate receptor 3 (GRM3).	[7]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE decreases the expression of Metabotropic glutamate receptor 3 (GRM3).	[8]

2 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 increases the methylation of Metabotropic glutamate receptor 3 (GRM3).	[5]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Metabotropic glutamate receptor 3 (GRM3).	[6]

References

• [1] 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.
• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [4] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Preferential induction of the AhR gene battery in HepaRG cells after a single or repeated exposure to heterocyclic aromatic amines. Toxicol Appl Pharmacol. 2010 Nov 15;249(1):91-100.