The evolutionary trace method Lichtarge et al., Proc Natl Acad Sci USA . 1996, 93, 7507 was applied to the adrenergic-receptor sequences. The conserved and ''conserved-in-class'' residues were determined for successive splits along the phylogenetic tree. These residues were then plotted on the internal and external faces of a model of the  -adrenergic receptor. The adrenergic-receptor model was constructed 2 using knowledge of the helix᎐helix packing angles in the cryoelectron microscopy structure of rhodopsin and the ideal ridges-in-grooves helix packing patterns known to Ž . reproduce these angles. Two clusters were observed on the external lipid-facing surface of the receptor model: a major one on helices 5 and 6 and a minor one on helices 2 and 3. The importance of some of the residues on helices 5 and 6 was confirmed by site-direceted mutagenesis. In contrast, very few residues were plotted on the external face of helices 1, 4, or 7. The major cluster is consistent with the dimerization interface in G-protein-coupled receptor domain-swapped dimers, which is proposed to occur between helices 5 and 6. The minor cluster is of unknown function. The clusters on the internal faces contain the known ligand-binding sites, as determined by site-directed mutagenesis. In particular, there is a line of conserved residues on helices 2᎐7 at a depth of about 14 A. On helices 2 and 3, and on 6 and 7, the cluster extends considerably deeper than the known binding site. These deeper clusters contain the conserved DRY and NPXXY motifs on helices 3 and 7, respectively, and so are probably related to receptor activation.