Resolving GPCR Activation and Signaling Dynamics by Solution NMR Spectroscopy

G protein-coupled receptors (GPCRs) are inherently dynamic transmembrane receptors that recognize various extracellular stimuli and mediate diverse signaling events. NMR spectroscopy is an important method to resolve the complex conformational energy landscapes of GPCRs and to probe the dynamic receptor-ligand/receptor-transducer interactions, which are critical in modulating functional diversity but are generally lacking in the static structures obtained by cryo-EM and X-ray crystallography studies. This review summarizes current advances in applying solution NMR to study GPCR structural dynamics during activation and signaling. We cover recent progress in sample preparation and isotopic labeling strategies, as well as critical NMR experimental methodologies that help illuminate transient interactions and functional intermediates. We then highlight representative studies that utilize the power of NMR to provide unique insights into GPCR signaling mechanisms that are difficult to access by other methods.