Opportunities and challenges for drug discovery in modulating Adhesion G protein-coupled receptor (GPCR) functions

Figures & data

Figure 1. Structural features of Adhesion G protein-coupled receptors. The subfamilies are listed as per the current classification [5] in the alphabetic order; the previously used numerical classification is referenced using Roman numbers in parentheses. The differentiation into autoproteolytic and non-autoproteolytic receptors is based on the cleavability profiles according to [35] and illustrated using different GPS coloration: yellow circle for receptors undergoing GPS-mediated autoproteolysis and white circle for receptors not undergoing autoproteolysis. Abbreviations: 7TM, 7-transmembrane domain; GAIN, GPCR autoproteolysis-inducing domain; GPS, GPCR proteolysis site; HRM, hormone receptor motif; IG, immunoglobulin; LRR, leucin-rich repeat; EGF, epidermal growth factor; SEA, sperm protein, enterokinase, agrin module; RBL, rhamnose-binding lectin; LMN, laminin; PXN, pentraxin; CUB, Cs1 and Csr/Uegf/BMP1 domain; TSP, thrombospondin; OFM, olfactomedin; LPHN, latrophillin; CDHN, cadherin; CALX, calnexin; EPTP, epitemptin

Figure 2. Compartmentation models of Adhesion G protein-coupled receptors structure. (a) The topology-based compartmentation model with an extracellular domain and intracellular domain separated by the 7TM domain. (b) The cleavage-based compartmentation model with an N-terminal fragment and a C-terminal fragment separated by the cleavable GPS motif. The compartmentation models are illustrated as per [15] and [16] on the examples of ADGRG1 and ADGRG5, two receptors with both agonist and antagonist molecules reported. Abbreviations: GPS, GPCR proteolysis site; 7TM, 7-transmembrane domain

Table 1. Current characterization of Adhesion G protein-coupled receptors

Subfamily name	Receptor name	GPS-mediated autoproteolysis	N-terminal interactions	Coupling partner(s)
Subfamily L	ADGRL1	Cleavable	α-laphrotoxin, teneurin-2, neurexin-1α, neurexin-1β, neurexin-2β, neurexin-3β, contactin-6, FLRT-1, FLRT-3, RECK	Gαs, Gαo, Gαq
	ADGRL2	Cleavable	FLRT‐3, teneurin‐2	None reported
	ADGRL3	Cleavable	Teneurin-3, UNC5A, FLRT-1, FLRT-3	cAMP
	ADGRL4	Cleavable	None reported	None reported
Subfamily E	ADGRE1	Non cleavable	None reported	None reported
	ADGRE2	Cleavable	Chondroitin sulfate B, Ab, constitutive activity	Gα15/16
	ADGRE3	Cleavable	None reported	None reported
	ADGRE4	Cleavable	None reported	None reported
	ADGRE5	Cleavable	Chondroitin sulfate B, CD55, CD90, Ab, LPAR1; constitutive activity	Gα12/13, RhoA, β-catenin
Subfamily A	ADGRA1	Not applicable -GAIN domain absent	None reported	None reported
	ADGRA2	Non cleavable	WNT-7, syndecan-1, syndecan-2, integrin‐αvβ3, heparin	Dlv, β-catenin, Clc42
	ADGRA3	Non cleavable	Constitutive activity	Dlv
Subfamily C	ADGRC1	Non cleavable	Vangl-2, frizzled-6	Rho kinase
	ADGRC2	Cleavable	ADGRC2 NTF	Ca^2+
	ADGRC3	Non cleavable	ADGRC3 NTF, frizzled-3; dystroglycan	Ca^2+
Subfamily D	ADGRD1	Cleavable	None reported	Gαs, cAMP
	ADGRD2	Non cleavable	None reported	None reported
Subfamily F	ADGRF1	Cleavable	Tethered peptide; N-DHA, 3-α-DOG; constitutive activity	Gαs, Gαq, cAMP
	ADGRF2	Non cleavable	None reported	None reported
	ADGRF3	Cleavable	None reported	None reported
	ADGRF4	Non cleavable	Tethered peptide; constitutive activity	Gα15, Gαq
	ADGRF5	Cleavable	Tethered peptide	Gαq/11, RhoA
Subfamily B	ADGRB1	Cleavable	Tethered peptide; phosphatidylserine, LPS, neuroligin-1, Nogo proteins; constitutive activity	ELMO/dock/Rac pathway, RhoA, β-arrestin, Gα12/13
	ADGRB2	Cleavable	Constitutive activity	Gα12/13, Gα15/16
	ADGRB3	Cleavable	C1qL1, C1qL2, C1qL3, C1qL4, stabilin-2	β-arrestin, ELMO/dock/Rac pathway
Subfamily G	ADGRG1	Cleavable	Tethered peptide; DHM, 3-DOG, collagen III, CD81, tissue transglutaminase 2, heparin, progastrin, L-Phe, plectin; Ab; constitutive activity	Gαq/11, Gα12/13,RhoA, β-arrestin, β-catenin
	ADGRG2	Cleavable	Tethered peptide; constitutive activity	Gαs, Gαq, Gα12/13, RhoA,
	ADGRG3	Cleavable	Beclomethasone, L-Phe, ezetimibe, zeranol, flunarizine; constitutive activity	Gαs, Gαi/o, RhoA, Cdc42, β‐arrestin
	ADGRG4	Cleavable	Constitutive activity	Gα12
	ADGRG5	Non cleavable	3-α-DOG, DHM; tethered peptide; constitutive activity	Gαs
	ADGRG6	Cleavable	PrP (C), collagen IV, laminin-211; tethered peptide; constitutive activity	Gαs, Gαi/o, Gαq/11
	ADGRG7	Non cleavable	None reported	None reported
Subfamily V	ADGRV1	Cleavable	Constitutive activity	Gαs, Gαi, Gαq

The table is presented as a summary of the currently available data on the aGPCR cleavability, N-terminal extracellular interactions and coupling partners, identified through analyzing the most recent review papers [6,7,35]. Abbreviations: GPS, GPCR proteolysis site; Ab, antibody; GAIN, GPCR autoproteolysis-inducing domain; Dlv, disheveled protein; NTF, N-terminal fragment; LPS, lipopolysaccharide; L-Phe, L-phenylalanin; N-DHA, N-docosahexaenoylethanolamine; 3-α-DOG, 3-α-acetoxydihydrodeoxygedunin; DHM, dihydromunduletone; PrP (C), cellular prion protein C

Table 2. Suggested Adhesion GPCR involvement in human diseases

Subfamily name	Receptor name	Involvement in disease
Subfamily L	ADGRL1	Breast cancer [74], NSCLC [75]; ADHD-like phenotype [118]
	ADGRL2	Urothelial carcinoma [76]
	ADGRL3	ADHD [113–117]; myocardial infarction [189], chronic renal disease [189]
	ADGRL4	Glioblastoma multiforme [77]
Subfamily E	ADGRE1	None reported
	ADGRE2	Breast cancer [78], glioblastoma multiforme [79]; vibratory angioedema [178]
	ADGRE3	Glioblastoma multiforme [80]; coronary artery disease [188]
	ADGRE4	None reported
	ADGRE5	Acute lymphatic leukemia [137,138], acute myeloid leukemia [139], gastric carcinoma [135], colorectal tumors [128], pancreatic carcinoma [135], esophageal carcinoma [135], gallbladder carcinoma [134], thyroid cancer [131], prostate cancer [136], glioblastoma multiforme [133], rhabdomyosarcoma [140], leiomyosarcoma [141], ovarian cancer [142], Burkitt lymphoma [143]
Subfamily A	ADGRA1	None reported
	ADGRA2	NSCLC [151]
	ADGRA3	None reported
Subfamily C	ADGRC1	B-cell leukemia [81], chronic lymphocytic leukemia [82], mantle cell leukemia [83], colorectal cancer [84], hepatocellular carcinoma [85], breast cancer [86]; craniorachischisis, spina bifida [109]; PMVSD, patent foramen ovale, double outlet right ventricle, transitional endocardial defect, tetralogy of Fallot, patent ductus arteriosus, VSD, ASD, pulmonary stenosis, MPVSD [109]
	ADGRC2	Spina bifida, anencephaly [109]; Ebstein’s anomaly, tricuspid incompetence, VSD, ASD, pulmonary stenosis, SASD [109]
	ADGRC3	CNS tumors [84]; craniorachischisis [109], Tourette syndrome [120–122]; tetralogy of Fallot, VSD, ASD, patent ductus arteriosus, patent foramen ovale [109]; T2DM [180]
Subfamily D	ADGRD1	None reported
	ADGRD2	None reported
Subfamily F	ADGRF1	Breast cancer [154], NSCLC [152], lung carcinoma [153], prostate carcinoma [153]
	ADGRF2	None reported
	ADGRF3	None reported
	ADGRF4	None reported
	ADGRF5	Breast cancer [87], NSCLC [88]; T2DM [179]
Subfamily B	ADGRB1	Glioblastoma [89], pulmonary adenocarcinoma [90], gastric cancer [91], colorectal cancer [92,93], breast cancer [94]
	ADGRB2	Colorectal cancer [95], osteosarcoma [96]; progressive spastic paraparesis [123]
	ADGRB3	Pulmonary tumors [97,98]; T2DM [181]
Subfamily G	ADGRG1	Acute myeloid leukemia [148,149], melanoma [132], NSCLC [145], glioblastoma multiforme [144], ovarian, cervical, breast, pancreatic, renal tumor [146], esophageal carcinoma [147]; bilateral frontoparietal polymicrogyria [102–106]; T2DM [183]
	ADGRG2	Ewing sarcoma [99], medulloblastoma [100]
	ADGRG3	None reported
	ADGRG4	GI neuroendocrine tumors [101]
	ADGRG5	None reported
	ADGRG6	AMC [157,158], AIS [160–164], AD [167]
	ADGRG7	None reported
Subfamily V	ADGRV1	Myoclonic seizures [124,125]; USH2 C [168,169,171–173]

The table serves as a summary of the current knowledge of aGPCRs’ potential involvement in human pathology as discussed throughout the review. Additional involvement in tumors, not covered in the main text is reported as per [73]. Abbreviations: NSCLC, non-small cell lung cancer; ADHD, attention deficit hyperactivity disorder; PMVSD, perimembranous ventricular septal defect; VSD, ventricular septal defect; ASD, atrial septal defect; PS, pulmonary stenosis; MPVSD, muscular portion ventricular septal defect; SASD, secundum atrial septal defect; T2DM, type 2 diabetes mellitus; GI, gastrointestinal; AMC, arthrogryposis multiplex congenita; AIS, adolescent idiopathic scoliosis; AD, aggressive periodontitis; USH2 C, type 2 C Usher syndrome.

Figure 3. Adhesion G protein-coupled receptors as therapeutic targets. The figure illustrates the currently recognized druggable sites as per [6] and schematically shows the molecular mechanisms of action for modulators included in the review. The colors signify sites that may be employed to develop aGPCR therapeutics: the extracellular domains of the N-terminal region are an attractive target for engineered antibodies (brown); the GAIN domain (green) may be potentially modifiable by protease modulators; the tethered peptide interaction site (red) is potentially targetable by peptide molecules; the 7TM domain, which is represented with seven blue transmembrane regions, is commonly targeted by small-molecule modulators (orange); and the PDZ binding motif in the C-terminal region is potentially targetable by small molecules to disrupt the PDZ scaffold protein interactions in some aGPCRs [6]. Abbreviations: GAIN, GPCR autoproteolysis-inducing domain; 7TM, 7-transmembrane domain; PDZ, PSD95/Dlg1/Zo-1 domain

Figure 4. Small molecule Adhesion G protein-coupled receptors modulators. The figure illustrates the small molecule modulators with known aGPCR modulatory activity. In 3-α-acetoxydihydrodeoxygedunin, the red color denotes the most crucial for activity part of the molecule overall, while the blue color indicates the moiety, reported to affect ADGRG1 binding the most; the asterisks indicate the positions of substituents [192]. In dihydromunduletone, the red color highlights the core component of the molecule, responsible for its flexibility [193]. The structures are available at: beclomethasone dipropionate [190] (PubChem CID: 21700), ezetimibe [191] (PubChem CID: 150311), flunarizine [191] (PubChem CID: 941361), zeranol [191] (PubChem CID: 2999413),3-α-acetoxydihydrodeoxygedunin [192] (PubChem CID not available), dihydromunduletone [193] (PubChem CID: 3492326), synaptamide [199] (PubChem CID: 5283451) and anandamide [199] (PubChem CID: 87246209). The structures are drawn in ChemDrawJS 18.1 (PerkinElmer Inc., USA) and composed in Adobe Illustrator CC 22.1

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