Fig. 3. Ligands in the vicinity of the classic orthosteric binding site of all family A GPCR crystal structures available in the protein structure databank: (a) ligands observed in the vicinity of the classic orthosteric binding sites of family A GPCR crystal structures after superimposing the receptor coordinates. Yellow stick: each ligand is represented by its mass center of the two heaviest moieties. Purple stick: inverse agonist BIIL260 observed in the leukotriene B4 (LTB4) receptor. Cyan stick: the mass center vector of BIIL260. (b) Extended view of the encircled region in A. An inverse agonist (purple stick) bound to the leukotriene B4 receptor in the crystal structure (PDB: 5X33) is extending to the region which was newly discovered in the present work. (c) Superimposed positions of the highly conserved W6.48 in the crystal structures of family A GPCRs. The χ1 angle of W6.48 can undergo 120° flipping which has a great impact on the volume changes induced by ligand binding to the adjacent orthosteric site. (d) Superposition of the normalized electrostatic potential surfaces of all ligands in the GPCR crystal structures deposited in the structure data bank, excluding ligand BIIL260. Left: side view and right: enlarged bottom view. White: hydrophobic areas. Red: negatively charged areas. Blue: positively charged areas. (e) The normalized electrostatic potential surface for BIIL260 in the leukotriene B4 (LTB4) receptor. White: hydrophobic area. Red: negatively charged area. Blue: positively charged area.
