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Vol. 56, Issue 5, 875-885, November 1999

Binding Pockets of the beta 1- and beta 2-Adrenergic Receptors for Subtype-Selective Agonists

Masafumi Isogaya,1 Yoshiyuki Sugimoto, Ryuji Tanimura, Rie Tanaka, Hideo Kikkawa,2 Taku Nagao, and Hitoshi Kurose

Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan (M.I., Y.S., Ri.T., H.Ki., T.N., H.Ku.); Toray Industries, Inc., Basic Research Laboratories, Kamakura, Kanagawa, Japan (Ry.T.)

We examined the subtype-selective binding site of the beta -adrenergic receptors (beta ARs). The beta 1/beta 2-chimeric receptors showed the importance of the second and seventh transmembrane domains (TM2 and TM7) of the beta 2AR for the binding of the beta 2-selective agonists such as formoterol and procaterol. Alanine-substituted mutants of TM7 of the beta 2AR showed that Tyr308, located at the top of TM7, mainly contributed to beta 2 selectivity. However, Tyr308 interacted with formoterol and procaterol in two different ways. The results of Ala- and Phe-substituted mutants indicated that the phenyl group of Tyr308 interacted with the phenyl group in the N-substituent of formoterol (hydrophobic interaction), and the hydroxyl group of Tyr308 interacted with the protonated amine of procaterol (hydrophilic interaction). In contrast to beta 2AR, TM2 is a major determinant that beta 1-selective agonists such as denopamine and T-0509 bound the beta 1AR with high affinity. Three amino acids (Leu110, Thr117, and Val120) in TM2 of the beta 1AR were identified as major determinants for beta 1-selective binding of these agonists. Three-dimensional models built on the basis of the predicted structure of rhodopsin showed that Tyr308 of the beta 2AR covered the binding pocket formed by TM2 and TM7 from the upper side, and Thr117 of the beta 1AR located in the middle of the binding pocket to provide a hydrogen bonding for the beta 1-selective agonists. These data indicate that TM2 and TM7 of the beta AR formed the binding pocket that binds the beta AR subtype-selective agonists with high affinity.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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