Figure 1.

(A) Conserved TM–fold of crystallized aminergic GPCRs (one crystal structure per receptor). The co-crystallized ligand doxepin (1) in H₁R is depicted using black carbon atoms. (B) Top view of the H₁R with doxepin (1, black carbon atoms). Magenta spheres depict C-alpha atoms from the binding pocket residues. The side chain of the key ionic anchor D^3.32 is displayed in black. Both the major and minor binding pocket are highlighted. (C) Sequence alignment of putative binding site residues of the human H₁R, human H₂R, human H₃R, human H₄R, human M₂R, rat and human M₃R (the pocket residues for M₃R rat and human are identical); human α₁AR, turkey α₁AR, human α₂AR and human D₃R. The lower case character preceding the receptor abbreviation indicates the species, h (human), r (rat) and m (turkey). Binding site residues are assigned based on the basis of 30 residues proposed by (Surgand et al., 2006) plus an additional 24 residues based on the six aminergic crystal structures and SDM studies (Table 1, Supporting Information Table S1) (Vroling et al., 2011). Residues in contact with the ligand in the crystal structure are coloured cyan. Magenta highlights residue W^7.40, which is an aminergic family specific conserved residue. The conserved residue D^3.32 is coloured red. Capital letters at the bottom indicate a partially conserved residue (>75%) and * indicates a fully conserved residue. All cysteines that form a disulphide bridge are highlighted in yellow.