Issue 1, 2018

Ligand-induced action of the W2866.48 rotamer toggle switch in the β2-adrenergic receptor

Abstract

Studies focused on GPCRs, particularly on the β2-adrenergic receptor (β2-AR), have demonstrated the relationship between ligand structure, receptor conformational changes and the corresponding pharmacological outcomes. Herein, we studied the molecular details of the rotameric flip of the W2866.48 sidechain, i.e. a presumed action switch that has not been reported in native β2-AR thus far. It is believed that although both the ‘active’ and ‘inactive’ conformers of β2-AR exhibit similar conformations of this switch, it may still play a substantial role in the ligand-induced activation of the receptor. By using both experimental methods (time-resolved fluorescence spectroscopy) and molecular modeling techniques (enhanced-sampling molecular dynamics), we characterized the conformational rearrangements of W2866.48 in relation to the type of ligand present in the binding cavity and to the conformation of the receptor (‘active’ vs. ‘inactive’ β2-AR). We found that the conformational behaviour of W2866.48 is correlated with the pharmacological character of the ligand present in the binding cavity but not with the instantaneous conformation of the receptor. Namely, agonists promote the W2866.48 conformations that facilitate the increase of the solvation within the inner receptor channel. In contrast, antagonists and inverse agonists act toward the decrease of the solvation in the inner channel. This creates an opportunity for using computational methodologies in determining the pharmacological properties of various ligands. The combination of the time-resolved fluorescence spectroscopy technique with the enhanced-sampling molecular dynamics simulations is shown to be a powerful tool for studying the ligand-induced conformational rearrangements in GPCRs.

Graphical abstract: Ligand-induced action of the W2866.48 rotamer toggle switch in the β2-adrenergic receptor

Supplementary files

Article information

Article type
Paper
Submitted
17 Jul 2017
Accepted
28 Nov 2017
First published
29 Nov 2017

Phys. Chem. Chem. Phys., 2018,20, 581-594

Ligand-induced action of the W2866.48 rotamer toggle switch in the β2-adrenergic receptor

A. Plazinska, W. Plazinski, R. Luchowski, A. Wnorowski, W. Grudzinski and W. I. Gruszecki, Phys. Chem. Chem. Phys., 2018, 20, 581 DOI: 10.1039/C7CP04808D

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements