Please use this identifier to cite or link to this item:
Title: Site-directed mutagenesis of the rat beta1-adrenoceptor. Involvement of Tyr356 (7.43) in (+/-)cyanopindolol but not (+/-)[125Iodo]cyanopindolol binding.
Austin Authors: Rezmann-Vitti, Linda A;Louis, Simon N S;Nero, Tracy L;Jackman, Graham P;Machida, Curtis A;Louis, William J 
Affiliation: Clinical Pharmacology and Therapeutics Unit, Department of Medicine, The University of Melbourne, Austin Health, Heidelberg, 3084 Victoria, Australia
Issue Date: 1-Jul-2004
Publication information: European Journal of Medicinal Chemistry; 39(7): 625-31
Abstract: To determine the role played by Tyr(356 (7.43)) in the rat beta(1)-adrenoceptor in binding the antagonists (+/-)cyanopindolol (4-[3-(t-butylamino]-3-(2'-cyano-indoloxy)-2-propanolol) and its iodinated analogue (+/-)[(125)Iodo]cyanopindolol (1-(t-butylamino]-3-(2'-cyano-3'-iodo-indoloxy)-2-propanolol), Tyr(356 (7.43)) was mutated to either Phe or Ala and binding affinities determined for wild type and mutant rat beta(1)-adrenoceptors. Our results indicate that Tyr(356 (7.43)) is important for (+/-)cyanopindolol, but not (+/-)[(125)Iodo]cyanopindolol, binding and that (+/-)cyanopindolol adopts a "reverse" binding orientation whereas (+/-)[(125)Iodo]cyanopindolol cannot be accommodated in this binding mode. We define a "reverse" antagonist binding mode as one where the aryloxy moiety interacts with residues on transmembrane helices 1, 2, 3 and 7. The beta(1)-adrenoceptor site-directed mutagenesis results are the first to support a "reverse" antagonist binding orientation and the involvement of Tyr(356 (7.43)) in this binding mode.
Gov't Doc #: 15236843
DOI: 10.1016/j.ejmech.2004.03.009
Journal: European journal of medicinal chemistry
Type: Journal Article
Subjects: Adrenergic beta-Antagonists.chemistry.metabolism.pharmacology
Iodine Radioisotopes
Models, Molecular
Mutagenesis, Site-Directed
Pindolol.analogs & derivatives.chemistry.metabolism.pharmacology
Protein Binding
Protein Conformation
Radioligand Assay
Receptors, Adrenergic, beta-1.genetics.metabolism
Appears in Collections:Journal articles

Show full item record

Page view(s)

checked on Jun 17, 2024

Google ScholarTM


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.