Role of Tyr356(7.43) and Ser190(4.57) in antagonist binding in the rat β1-adrenergic receptor

Linda A. Rezmann-Vitti, Tracy L. Nero, Graham P. Jackman, Curtis A. Machida, Brian J. Duke, William J. Louis, Simon N.S. Louis

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Site-directed mutagenesis and photoaffinity labeling experiments suggest the existence of at least two distinct binding orientations for aryloxypropanolamine competitive antagonists in the β-adrenergic receptor (β-AR), one where the aryloxy moiety is located near transmembrane α-helix 7 (tm 7) and another where it is near tm 5. To explore a hydrophobic pocket involving tms 1, 2, 3, and 7 for potential aryloxy interaction sites, we selected Tyr356(7.43) and Trp 134(3.28) in the rat β1-AR for site-directed mutagenesis studies. Ser190(4.57) was also investigated, as the equivalent residues are known antagonist interaction sites in the muscarinic M1 and the dopamine D2 receptors. Binding affinities (pKi) of a series of structurally diverse aryloxypropanolamine competitive antagonists were determined for wild type and Y356A, Y356F, W134A, and S190A mutant rat β1-ARs stably expressed in Chinese hamster ovary cells. To visualize possible antagonist/receptor interactions, the compounds were docked into a three-dimensional model of the wild-type rat β1-AR. The results indicate that Tyr356(7.43) is an important aromatic interaction site for five of the eight competitive antagonists studied, whereas none of the compounds appeared to interact directly with Trp134(3.28). Only two of the competitive antagonists interacted with Ser190(4.57) on tm 4. Overall, the results extend our understanding of how β1-AR competitive antagonists bind to the hydrophobic pocket involving tms 1, 2, 3, and 7; highlight the importance of Tyr356(7.43) in this binding pocket; and demonstrate the involvement of tm 4 in competitive antagonist binding.

Original languageEnglish (US)
Pages (from-to)3467-3477
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number12
StatePublished - Jun 15 2006
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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