TABLE 1

X-ray structures of class A and B GPCRs in which the allosteric ligands are bound to transmembrane lipid-facing binding sites, which can be accessed only through lipid pathways

GPCR Class	Receptor	Allosteric Ligand Name	PDB ID	Bilayer Depth (Å)^{^a}			Major Species at pH 7.4	Solvent-Accessible Surface Area (SASA)^{^b}
					Ligand Lipophilicity			Unbound Ligand			Bound Ligand
					C log P	log D_7.4		Total (Å²)	Polar (%)	Nonpolar (%)	MESA (%)	BSA (%)
A	GPR40	TAK-875^{^c}	4PHU	16.1	1.30	1.23	Negative	656.5	49.8	50.2	31	69
	GPR40	MK-8666^{^c}	5TZR	16.4	3.75	1.62	Negative	913.4	16.8	83.2	34	66
	GPR40	AP8^{^d}	5TZY	30.5	5.23	4.05	Zwitterionic	923.9	15.6	84.4	34	66
	P2Y₁	BPTU^{^e}	4XNV	22.7	7.50	5.53	Neutral	739.8	34.8	65.2	40	60
	PAR2	AZ3451^{^e}	5NDZ	18.0	7.96	6.37	Neutral	773.1	18.1	81.9	43	57
B	CRF1R	CP-376395^{^e}	4K5Y	23.6	7.61	5.7	Positive	658.1	49.4	50.6	39	61
	GCGR	MK-0893^{^e}	5EE7	31.6	4.88	3.42	Negative	971.6	9.9	90.1	44	56
	GLP1R	PF-06372222^{^f}	5VEW	34.7	4.61	−0.53	Negative	908.3	13.3	86.7	30	70
	GLP1R	NNC0640^{^f}	5VEX	31.0	4.08	1.28	Positive	976.2	41.5	58.5	45	55

CRF1R, corticotropin-releasing factor 1 receptor; GLP1R, glucagon-like peptide 1 receptor; GPR40, free fatty acid receptor 1; PAR2, protease-activated receptor 2.
↵^a Binding site location (bilayer depth) within the membrane, measured as the distance between center of mass (COM) of the ligand and that of the phosphorus atoms in the upper leaflet, measured along the bilayer normal.
↵^b Calculated using NACCESS (Hubbard and Thornton, 1993) with a probe of radius 1.4 Å; C log P: 1-octanol/water partition coefficients calculated using Bio-Loom for Windows version 1.5 (2006); log D_7.4: partition coefficient at pH 7.4 that was calculated using ACD/Percepta (Advanced Chemistry Development, Inc., Toronto, ON, 2015). For bilayer depth calculation, the membrane-embedded crystal structures were obtained from the OPM database (Lomize et al., 2012). The average bilayer thickness was 36.92 Å for all the studied receptors.
↵^c Partial agonist.
↵^d Full allosteric agonists, AgoPAMs.
↵^e Antagonist.
↵^f Negative allosteric modulator.