Conformational Complexity and Dynamics in a Muscarinic Receptor Revealed by NMR Spectroscopy

Journal article


Publication Details

Author(s): Xu J, Hu Y, Kaindl J, Risel P, Hübner H, Maeda S, Niu X, Li H, Gmeiner P, Jin C, Kobilka BK
Journal: Molecular Cell
Publication year: 2019
Volume: 75
Journal issue: 1
Pages range: 53-65.e7
ISSN: 1097-2765


Abstract

The M2 muscarinic acetylcholine receptor (M2R) is a prototypical GPCR that plays important roles in regulating heart rate and CNS functions. Crystal structures provide snapshots of the M2R in inactive and active states, but the allosteric link between the ligand binding pocket and cytoplasmic surface remains poorly understood. Here we used solution NMR to examine the structure and dynamics of the M2R labeled with 13CH3-ε-methionine upon binding to various orthosteric and allosteric ligands having a range of efficacy for both G protein activation and arrestin recruitment. We observed ligand-specific changes in the NMR spectra of 13CH3-ε-methionine probes in the M2R extracellular domain, transmembrane core, and cytoplasmic surface, allowing us to correlate ligand structure with changes in receptor structure and dynamics. We show that the M2R has a complex energy landscape in which ligands with different efficacy profiles stabilize distinct receptor conformations. Xu et al. reveal that the M2 muscarinic receptor is highly dynamic, with a complex energy landscape in which ligands with different signaling profiles stabilize distinct receptor conformations.


FAU Authors / FAU Editors

Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie
Kaindl, Jonas
Lehrstuhl für Pharmazeutische Chemie
Risel, Philipp
Lehrstuhl für Pharmazeutische Chemie


External institutions with authors

Peking University (PKU) / 北京大学
Stanford University
Tsinghua University


How to cite

APA:
Xu, J., Hu, Y., Kaindl, J., Risel, P., Hübner, H., Maeda, S.,... Kobilka, B.K. (2019). Conformational Complexity and Dynamics in a Muscarinic Receptor Revealed by NMR Spectroscopy. Molecular Cell, 75(1), 53-65.e7. https://dx.doi.org/10.1016/j.molcel.2019.04.028

MLA:
Xu, Jun, et al. "Conformational Complexity and Dynamics in a Muscarinic Receptor Revealed by NMR Spectroscopy." Molecular Cell 75.1 (2019): 53-65.e7.

BibTeX: 

Last updated on 2019-16-07 at 08:38