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J. Biol. Chem., Vol. 264, Issue 23, 13572-13578, Aug, 1989
CD Strader, MR Candelore, WS Hill, IS Sigal and RA Dixon
Pharmacophore mapping of the ligand binding domain of the beta- adrenergic
receptor has revealed specific molecular interactions which are important
for agonist and antagonist binding to the receptor. Previous site-directed
mutagenesis experiments have demonstrated that the binding of amine
agonists and antagonists to the receptor involves an interaction between
the amine group of the ligand and the carboxylate side chain of Asp113 in
the third hydrophobic domain of the receptor (Strader, C. D., Sigal, I. S.,
Candelore, M. R., Rands, E., Hill, W. S., and Dixon, R. A. F. (1988) J.
Biol. Chem. 263, 10267- 10271). We have now identified 2 serine residues,
at positions 204 and 207 in the fifth hydrophobic domain of the
beta-adrenergic receptor, which are critical for agonist binding and
activation of the receptor. These serine residues are conserved with
G-protein-coupled receptors which bind catecholamine agonists, but not with
receptors whose endogenous ligands do not have the catechol moiety. Removal
of the hydroxyl side chain from either Ser204 or Ser207 by substitution of
the serine residue with an alanine attenuates the activity of catecholamine
agonists at the receptor. The effects of these mutations on agonist
activity are mimicked selectively by the removal of the catechol hydroxyl
moieties from the aromatic ring of the agonist. The data suggest that the
interaction of catecholamine agonists with the beta- adrenergic receptor
involves two hydrogen bonds, one between the hydroxyl side chain of Ser204
and the meta-hydroxyl group of the ligand and a second between the hydroxyl
side chain of Ser207 and the para- hydroxyl group of the ligand.
Identification of two serine residues involved in agonist activation of the beta-adrenergic receptor
Department of Molecular Pharmacology and Biochemistry, Merck, Sharp, and Dohme Research Laboratories, Rahway, New Jersey 07065.
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J. Hwa, R. M. Graham, and D. M. Perez Identification of Critical Determinants of alpha(1)-Adrenergic Receptor Subtype Selective Agonist Bind |
