Binding pockets of the β1- and β1-adrenergic receptors for subtype- selective agonists

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

Research output: Contribution to journalArticlepeer-review

40 Citations (Scopus)


We examined the subtype-selective binding site of the β-adrenergic receptors (βARs). The β12-chimeric receptors showed the importance of the second and seventh transmembrane domains (TM2 and TM7) of the β2AR for the binding of the β2-selective agonists such as formoterol and procaterol. Alanine-substituted mutants of TM7 of the β2AR showed that Tyr308 located at the top of TM7, mainly contributed to β2 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 β2AR, TM2 is a major determinant that β1-selective agonists such as denopamine and T-0509 bound the β1AR with high affinity. Three amino acids (Leu110, Thr117, and Val120) in TM2 of the β1AR were identified as major determinants for β1-selective binding of these agonists. Three-dimensional models built on the basis of the predicted structure of rhodopsin showed that Tyr308 of the β2AR covered the binding pocket formed by TM2 and TM7 from the upper side, and Thr117 of the β1AR located in the middle of the binding pocket to provide a hydrogen bonding for the β1-selective agonists. These data indicate that TM2 and TM7 of the βAR formed the binding pocket that binds the βAR subtype-selective agonists with high affinity.

Original languageEnglish
Pages (from-to)875-885
Number of pages11
JournalMolecular Pharmacology
Issue number5
Publication statusPublished - 1999
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology


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