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The Isoleucine at Position 118 in Transmembrane 2 Is Responsible for the Selectivity of Xamoterol, Nebivolol, and ICI89406 for the Human β1-Adrenoceptor

Lim, Victor Jun Yu; Proudman, Richard George William; Monteleone, Stefania; Kolb, Peter; Baker, Jillian G.


Victor Jun Yu Lim

Richard George William Proudman

Stefania Monteleone

Peter Kolb

Professor of Drug Discovery and Respiratory Medicine


Known off-target interactions frequently cause predictable drug side-effects (e.g., β1-antagonists used for heart disease, risk β2-mediated bronchospasm). Computer-aided drug design would improve if the structural basis of existing drug selectivity was understood. A mutagenesis approach determined the ligand-amino acid interactions required for β1-selective affinity of xamoterol and nebivolol, followed by computer-based modeling to provide possible structural explanations. 3H-CGP12177 whole cell binding was conducted in Chinese hamster ovary cells stably expressing human β1, β2, and chimeric β1/β2-adrenoceptors (ARs). Single point mutations were investigated in transiently transfected cells. Modeling studies involved docking ligands into three-dimensional receptor structures and performing molecular dynamics simulations, comparing interaction frequencies between apo and holo structures of β1 and β2-ARs. From these observations, an ICI89406 derivative was investigated that gave further insights into selectivity. Stable cell line studies determined that transmembrane 2 was crucial for the β1-selective affinity of xamoterol and nebivolol. Single point mutations determined that the β1-AR isoleucine (I118) rather than the β2 histidine (H93) explained selectivity. Studies of other β1-ligands found I118 was important for ICI89406 selective affinity but not that for betaxolol, bisoprolol, or esmolol. Modeling studies suggested that the interaction energies and solvation of β1-I118 and β2-H93 are factors determining selectivity of xamoterol and ICI89406. ICI89406 without its phenyl group loses its high β1-AR affinity, resulting in the same affinity as for the β2-AR. The human β1-AR residue I118 is crucial for the β1-selective affinity of xamoterol, nebivolol, and ICI89406 but not all β1-selective compounds. SIGNIFICANCE STATEMENT: Some ligands have selective binding affinity for the human β1 versus the β2-adrenoceptor; however, the molecular/structural reason for this is not known. The transmembrane 2 residue isoleucine I118 is responsible for the selective β1-binding of xamoterol, nebivolol, and ICI89406 but does not explain the selective β1-binding of betaxolol, bisoprolol, or esmolol. Understanding the structural basis of selectivity is important to improve computer-aided ligand design, and targeting I118 in β1-adrenoceptors is likely to increase β1-selectivity of drugs.


Lim, V. J. Y., Proudman, R. G. W., Monteleone, S., Kolb, P., & Baker, J. G. (2023). The Isoleucine at Position 118 in Transmembrane 2 Is Responsible for the Selectivity of Xamoterol, Nebivolol, and ICI89406 for the Human β1-Adrenoceptor. Molecular Pharmacology, 103(2), 89-99.

Journal Article Type Article
Acceptance Date Oct 19, 2022
Online Publication Date Jan 19, 2023
Publication Date Feb 1, 2023
Deposit Date Nov 23, 2022
Publicly Available Date Jan 19, 2023
Journal Molecular Pharmacology
Print ISSN 0026-895X
Electronic ISSN 1521-0111
Publisher American Society for Pharmacology and Experimental Therapeutics
Peer Reviewed Peer Reviewed
Volume 103
Issue 2
Pages 89-99
Keywords Pharmacology; Molecular Medicine
Public URL
Publisher URL
Additional Information Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY Attribution 4.0 International license.


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