Conformational Complexity and Dynamics in a GPCR Revealed by NMR Spectroscopy
59 Pages Posted: 26 Feb 2019 Publication Status: Review CompleteMore...
The M2 muscarinic acetylcholine receptor (M2R) is a prototypical GPCR that plays important roles in regulating heart rate and central nerves system functions. Crystal structures provide snapshots of the M2R in inactive and active states; yet the allosteric link between the ligand binding pocket and cytoplasmic surface remains poorly understood. Here we employed solution NMR to examine the structure and dynamics of the M2R labeled with 13CH3-ɛ-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-ɛ-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 where ligands with different efficacy profiles stabilize distinct receptor conformations.
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