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

Xu J, Hu Y, Kaindl J, Risel P, Hübner H, Maeda S, Niu X, Li H, Gmeiner P, Jin C, Kobilka BK (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Book Volume: 75

Pages Range: 53-65.e7

Journal Issue: 1

DOI: 10.1016/j.molcel.2019.04.028

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.

Authors with CRIS profile

Additional Organisation(s)

Involved external institutions

Peking University (PKU) / 北京大学 China (CN) Tsinghua University China (CN) Stanford University United States (USA) (US)

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.

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