Journal article
(Original article)


Molecular dynamics simulations of the effect of the G-protein and diffusible ligands on the β2-adrenergic receptor


Publication Details
Author(s): Goetz A, Lanig H, Gmeiner P, Clark T
Publisher: Elsevier
Publication year: 2011
Volume: 414
Journal issue: 4
Pages range: 611-623
ISSN: 0022-2836
Language: English

Abstract

G-protein-coupled receptors have extraordinary therapeutic potential as targets for a broad spectrum of diseases. Understanding their function at the molecular level is therefore essential. A variety of crystal structures have made the investigation of the inactive receptor state possible. Recently released X-ray structures of opsin and the β -adrenergic receptor (β AR) have provided insight into the active receptor state. In addition, we have contributed to the crystal structure of an irreversible agonist-β adrenoceptor complex. These extensive studies and biophysical investigations have revealed that agonist binding leads to a low-affinity conformation of the active state that is suggested to facilitate G-protein binding. The high-affinity receptor state, which promotes signal transduction, is only formed in the presence of both agonist and G-protein. Despite numerous crystal structures, it is not yet clear how ligands tune receptor dynamics and G-protein binding. We have now used molecular dynamics simulations to elucidate the distinct impact of agonist and inverse agonist on receptor conformation and G-protein binding by investigating the influence of the ligands on the structure and dynamics of a complex composed of β AR and the C-terminal end of the Gα subunit (GαCT). The simulations clearly showed that the agonist isoprenaline and the inverse agonist carazolol influence the ligand-binding site and the interaction between β AR and GαCT differently. Isoprenaline induced an inward motion of helix 5, whereas carazolol blocked the rearrangement of the extracellular part of the receptor. Moreover, in the presence of isoprenaline, β AR and GαCT form a stable interaction that is destabilized by carazolol. © 2011 Elsevier Ltd. All rights reserved.



How to cite
APA: Goetz, A., Lanig, H., Gmeiner, P., & Clark, T. (2011). Molecular dynamics simulations of the effect of the G-protein and diffusible ligands on the β2-adrenergic receptor. Journal of Molecular Biology, 414(4), 611-623. https://dx.doi.org/10.1016/j.jmb.2011.10.015

MLA: Goetz, Angela, et al. "Molecular dynamics simulations of the effect of the G-protein and diffusible ligands on the β2-adrenergic receptor." Journal of Molecular Biology 414.4 (2011): 611-623.

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