Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTU8GU9M)

• DOT Name: Type-2 angiotensin II receptor (AGTR2)
• Synonyms: Angiotensin II type-2 receptor; AT2 receptor
• Gene Name: AGTR2
• Related Disease:
  Non-syndromic X-linked intellectual disability
  X-linked complex neurodevelopmental disorder
• UniProt ID: AGTR2_HUMAN
• PDB ID: 5UNF; 5UNG; 5UNH; 5XJM; 6JOD; 7C6A; 7JNI
• Pfam ID: PF00001
• Sequence:
  MKGNSTLATTSKNITSGLHFGLVNISGNNESTLNCSQKPSDKHLDAIPILYYIIFVIGFL
  VNIVVVTLFCCQKGPKKVSSIYIFNLAVADLLLLATLPLWATYYSYRYDWLFGPVMCKVF
  GSFLTLNMFASIFFITCMSVDRYQSVIYPFLSQRRNPWQASYIVPLVWCMACLSSLPTFY
  FRDVRTIEYLGVNACIMAFPPEKYAQWSAGIALMKNILGFIIPLIFIATCYFGIRKHLLK
  TNSYGKNRITRDQVLKMAAAVVLAFIICWLPFHVLTFLDALAWMGVINSCEVIAVIDLAL
  PFAILLGFTNSCVNPFLYCFVGNRFQQKLRSVFRVPITWLQGKRESMSCRKSSSLREMET
  FVS
• Function: Receptor for angiotensin II, a vasoconstricting peptide. Signals primarily via a non-canonical G-protein- and beta-arrestin independent pathways. Cooperates with MTUS1 to inhibit ERK2 activation and cell proliferation.
• Tissue Specificity: In adult, highly expressed in myometrium with lower levels in adrenal gland and fallopian tube. Expressed in the cerebellum. Very highly expressed in fetal kidney and intestine.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Renin-angiotensin system (hsa04614)
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Peptide ligand-binding receptors (R-HSA-375276)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-syndromic X-linked intellectual disability	DIS71AI3	Supportive	X-linked	[1]
X-linked complex neurodevelopmental disorder	DISI3QE9	Disputed	X-linked	[2]

1 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 Type-2 angiotensin II receptor (AGTR2).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate affects the expression of Type-2 angiotensin II receptor (AGTR2).	[4]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Type-2 angiotensin II receptor (AGTR2).	[5]
Menthol	DMG2KW7	Approved	Menthol decreases the expression of Type-2 angiotensin II receptor (AGTR2).	[6]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Type-2 angiotensin II receptor (AGTR2).	[7]
Coprexa	DMA0WEK	Phase 3	Coprexa decreases the expression of Type-2 angiotensin II receptor (AGTR2).	[8]
Paraquat	DMR8O3X	Investigative	Paraquat decreases the expression of Type-2 angiotensin II receptor (AGTR2).	[9]

References

• [1] Identification of two AGTR2 mutations in male patients with non-syndromic mental retardation. Hum Genet. 2004 Jan;114(2):211-3. doi: 10.1007/s00439-003-1048-8. Epub 2003 Nov 4.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] 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.
• [4] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [5] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [6] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [7] 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.
• [8] Copper chelator ATN-224 inhibits endothelial function by multiple mechanisms. Microvasc Res. 2009 May;77(3):314-26.
• [9] Paraquat increases connective tissue growth factor and collagen expression via angiotensin signaling pathway in human lung fibroblasts. Toxicol In Vitro. 2010 Apr;24(3):803-8. doi: 10.1016/j.tiv.2009.12.015. Epub 2009 Dec 24.