NDLI: Involvement of Asn-293 in stereospecific agonist recognition and in activation of the beta 2-adrenergic receptor.

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Involvement of Asn-293 in stereospecific agonist recognition and in activation of the beta 2-adrenergic receptor.

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Involvement of Asn-293 in stereospecific agonist recognition and in activation of the beta 2-adrenergic receptor.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Lohse, M. J. Ijzerman, A. P. Wieland, K. Zuurmond, H. M. Krasel, C.
Description	Author Affiliation: Wieland K ( Department of Pharmacology, University of Würzburg, Germany.);
Abstract	To investigate the molecular mechanism for stereospecific binding of agonists to beta 2-adrenergic receptors we used receptor models to identify potential binding sites for the beta-OH-group of the ligand, which defines the chiral center. Ser-165, located in transmembrane helix IV, and Asn-293, situated in the upper half of transmembrane helix VI, were identified as potential binding sites. Mutation of Ser-165 to Ala did not change the binding of either isoproterenol isomer as revealed after transient expression in human embryonic kidney (HEK)-293 cells. In contrast, a receptor mutant in which Asn-293 was replaced by Leu showed substantial loss of stereospecific isoproterenol binding. Adenylyl cyclase stimulation by this mutant after stable expression in CHO cells confirmed the substantial loss of stereospecificity for isoproterenol. In a series of agonists the loss of affinity in the Leu-293 mutant receptor was strongly correlated with the intrinsic activity of the compounds. Full agonists showed a 10-30-fold affinity loss, whereas partial agonists had almost the same affinity for both receptors. Stereospecific recognition of antagonists was unaltered in the Leu-293 mutant receptor. These data indicate a relationship between stereospecificity and intrinsic activity of agonists and suggest that Asn-293 is important for both properties of the agonist-receptor interaction.
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	17
Volume Number	93
Language	English
Publisher	National Academy of Sciences
Publisher Date	1996-10-01
Publisher Place	United States
Access Restriction	Open
Subject Keyword	Adrenergic Beta-Agonists Metabolism Isoproterenol Receptors, Adrenergic, Beta-2 Adenylate Cyclase Drug Effects Adrenergic Beta-2 Receptor Agonists Alprenolol Animals Asparagine Genetics Binding Sites CHO Cells Computer Simulation Cricetinae Chemistry Pharmacology Metoprolol Models, Molecular Mutagenesis, Site-Directed Mutation Propranolol Serine Signal Transduction Stereoisomerism Comparative Study Research Support, Non-U.S. Gov't Multidisciplinary
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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