Structural basis of β‐adrenergic receptor function

Abstract

Receptors that mediate their actions by stimulating guanine nucleotide binding regulatory proteins (G proteins) share structural as well as functional similarities. The structural motif characteristic of receptors of this class includes seven hydrophobic putative transmembrane domains linked by hydrophilic loops. Genetic analysis of the β‐adrenergic receptor (βAR) revealed that the ligand binding domain of this receptor, like that of rhodopsin, involves residues within the hydrophobic core of the protein. On the basis of these studies, a model for ligand binding to the receptor has been developed in which the amino group of an agonist or antagonist is anchored to the receptor through the carboxylate side chain of Asp 113 in the third transmembrane helix. Other interactions between specific residues of the receptor and functional groups on the ligand have also been proposed. The interaction between the βAR and the G protein G s has been shown to involve an intracellular region that is postulated to form an amphi‐philic α helix. This region of the βAR is also critical for sequestration, which accompanies agonist‐mediated desensitization, to occur. Structural similarities among G protein‐linked receptors suggest that the information gained from the genetic analysis of the βAR should help define functionally important regions of other receptors of this class.— S trader , C. D.; S igal , I. S.; D ixon , R. A. F. Structural basis of β‐adrenergic receptor function. FASEB J. 3: 1825‐1832; 1989.