Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYME7VD)

• DOT Name: G-protein coupled receptor 84 (GPR84)
• Synonyms: Inflammation-related G-protein coupled receptor EX33
• Gene Name: GPR84
• UniProt ID: GPR84_HUMAN
• PDB ID: 8G05; 8J18; 8J19; 8J1A
• Pfam ID: PF00001
• Sequence:
  MWNSSDANFSCYHESVLGYRYVAVSWGVVVAVTGTVGNVLTLLALAIQPKLRTRFNLLIA
  NLTLADLLYCTLLQPFSVDTYLHLHWRTGATFCRVFGLLLFASNSVSILTLCLIALGRYL
  LIAHPKLFPQVFSAKGIVLALVSTWVVGVASFAPLWPIYILVPVVCTCSFDRIRGRPYTT
  ILMGIYFVLGLSSVGIFYCLIHRQVKRAAQALDQYKLRQASIHSNHVARTDEAMPGRFQE
  LDSRLASGGPSEGISSEPVSAATTQTLEGDSSEVGDQINSKRAKQMAEKSPPEASAKAQP
  IKGARRAPDSSSEFGKVTRMCFAVFLCFALSYIPFLLLNILDARVQAPRVVHMLAANLTW
  LNGCINPVLYAAMNRQFRQAYGSILKRGPRSFHRLH
• Function: G protein-coupled receptor that responds endogenously to dietary fatty acids or nutrient, specifically medium-chain free fatty acid (FFA) with carbon chain lengths of C9 to C14. Capric acid (C10:0), undecanoic acid (C11:0) and lauric acid (C12:0) are the most potent agonists. In immune cells, functions as a pro-inflammatory receptor via 6-OAU and promotes the expression of pro-inflammatory mediators such as TNFalpha, IL-6 and IL-12B as well as stimulating chemotactic responses through activation of signaling mediators AKT, ERK and NF-kappa-B. In addition, triggers increased bacterial adhesion and phagocytosis in macrophages and regulates pro-inflammatory function via enhancing NLRP3 inflammasome activation. Plays also an important role in inflammation by modulating neutrophil functions. Mechanistically, promotes neutrophil chemotaxis, reactive oxygen species (ROS) production and degranulation via LYN-AKT/ERK pathway. To regulate ROS, communicates with the two formyl peptide receptors FPR2 and FPR1 to control the NADPH oxidase activity in neutrophils.
• Tissue Specificity: Expressed predominantly in hematopoietic tissues. High levels detected in the bone marrow and lower levels in the peripheral leukocytes and lung. Also expressed in brain, heart, muscle, colon, thymus, splen, kidney, liver, placenta and intestine. Within the leukocyte population expression is higher in neutrophils and eosinophils relative to T- or B-lymphocytes.
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  G alpha (s) signalling events (R-HSA-418555)

Molecular Interaction Atlas (MIA) of This DOT

4 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 G-protein coupled receptor 84 (GPR84).	[1]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of G-protein coupled receptor 84 (GPR84).	[2]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of G-protein coupled receptor 84 (GPR84).	[3]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of G-protein coupled receptor 84 (GPR84).	[4]

References

• [1] 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.
• [2] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [3] Expression of endogenous retroviruses reflects increased usage of atypical enhancers in T cells. EMBO J. 2019 Jun 17;38(12):e101107. doi: 10.15252/embj.2018101107. Epub 2019 May 8.
• [4] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.