Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5ID1DZ)

• DOT Name: Metabotropic glutamate receptor 4 (GRM4)
• Synonyms: mGluR4
• Gene Name: GRM4
• UniProt ID: GRM4_HUMAN
• PDB ID: 7E9H; 8JD4; 8JD5; 8JD6
• Pfam ID: PF00003 ; PF01094 ; PF07562
• Sequence:
  MPGKRGLGWWWARLPLCLLLSLYGPWMPSSLGKPKGHPHMNSIRIDGDITLGGLFPVHGR
  GSEGKPCGELKKEKGIHRLEAMLFALDRINNDPDLLPNITLGARILDTCSRDTHALEQSL
  TFVQALIEKDGTEVRCGSGGPPIITKPERVVGVIGASGSSVSIMVANILRLFKIPQISYA
  STAPDLSDNSRYDFFSRVVPSDTYQAQAMVDIVRALKWNYVSTVASEGSYGESGVEAFIQ
  KSREDGGVCIAQSVKIPREPKAGEFDKIIRRLLETSNARAVIIFANEDDIRRVLEAARRA
  NQTGHFFWMGSDSWGSKIAPVLHLEEVAEGAVTILPKRMSVRGFDRYFSSRTLDNNRRNI
  WFAEFWEDNFHCKLSRHALKKGSHVKKCTNRERIGQDSAYEQEGKVQFVIDAVYAMGHAL
  HAMHRDLCPGRVGLCPRMDPVDGTQLLKYIRNVNFSGIAGNPVTFNENGDAPGRYDIYQY
  QLRNDSAEYKVIGSWTDHLHLRIERMHWPGSGQQLPRSICSLPCQPGERKKTVKGMPCCW
  HCEPCTGYQYQVDRYTCKTCPYDMRPTENRTGCRPIPIIKLEWGSPWAVLPLFLAVVGIA
  ATLFVVITFVRYNDTPIVKASGRELSYVLLAGIFLCYATTFLMIAEPDLGTCSLRRIFLG
  LGMSISYAALLTKTNRIYRIFEQGKRSVSAPRFISPASQLAITFSLISLQLLGICVWFVV
  DPSHSVVDFQDQRTLDPRFARGVLKCDISDLSLICLLGYSMLLMVTCTVYAIKTRGVPET
  FNEAKPIGFTMYTTCIVWLAFIPIFFGTSQSADKLYIQTTTLTVSVSLSASVSLGMLYMP
  KVYIILFHPEQNVPKRKRSLKAVVTAATMSNKFTQKGNFRPNGEAKSELCENLEAPALAT
  KQTYVTYTNHAI
• 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: Strongly expressed in the cerebellum. Expressed at low levels in hippocampus, hypothalamus and thalamus. No expression detected in liver.
• KEGG Pathway:
  Phospholipase D sig.ling pathway (hsa04072)
  Neuroactive ligand-receptor interaction (hsa04080)
  Glutamatergic sy.pse (hsa04724)
  Taste transduction (hsa04742)
• Reactome Pathway:
  Class C/3 (Metabotropic glutamate/pheromone receptors) (R-HSA-420499)
  Sensory perception of sweet, bitter, and umami (glutamate) taste (R-HSA-9717207)
  G alpha (i) signalling events (R-HSA-418594)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Metabotropic glutamate receptor 4 (GRM4).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Metabotropic glutamate receptor 4 (GRM4).	[3]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the methylation of Metabotropic glutamate receptor 4 (GRM4).	[4]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Afimoxifene	DMFORDT	Phase 2	Afimoxifene increases the expression of Metabotropic glutamate receptor 4 (GRM4).	[2]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of Metabotropic glutamate receptor 4 (GRM4).	[5]
Deguelin	DMXT7WG	Investigative	Deguelin decreases the expression of Metabotropic glutamate receptor 4 (GRM4).	[6]
2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE	DMNQL17	Investigative	2-AMINO-1-METHYL-6-PHENYLIMIDAZO[4,5-B]PYRIDINE increases the expression of Metabotropic glutamate receptor 4 (GRM4).	[7]
4-[1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenol	DMTMLXU	Investigative	4-[1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]phenol decreases the expression of Metabotropic glutamate receptor 4 (GRM4).	[2]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID20638279C11	DMFHS4V	Investigative	PMID20638279C11 affects the binding of Metabotropic glutamate receptor 4 (GRM4).	[8]

References

• [1] 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.
• [2] Molecular mechanism of action of bisphenol and bisphenol A mediated by oestrogen receptor alpha in growth and apoptosis of breast cancer cells. Br J Pharmacol. 2013 May;169(1):167-78.
• [3] 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.
• [4] 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.
• [5] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [6] Neurotoxicity and underlying cellular changes of 21 mitochondrial respiratory chain inhibitors. Arch Toxicol. 2021 Feb;95(2):591-615. doi: 10.1007/s00204-020-02970-5. Epub 2021 Jan 29.
• [7] 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.
• [8] An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction. Bioorg Med Chem Lett. 2010 Aug 15;20(16):4901-5.