The role of NMR spectroscopy in mapping the conformational landscape of GPCRs

•Using multiple labelling strategies, NMR spectroscopy provides insights into the dynamic nature of several class A GPCRs.•Receptors populate a range of states that are in equilibra determined by a complex energy landscape.•General features as well as receptor-specific differences in GPCR allosteric activation are observed.•Agonist binding to a receptor influences the exchange kinetics as well as the population of different states.•Full agonist bound states are observed to be particularly dynamic. Over recent years, nuclear magnetic resonance (NMR) spectroscopy has developed into a powerful mechanistic tool for the investigation of G protein-coupled receptors (GPCRs). NMR provides insights which underpin the dynamic nature of these important receptors and reveals experimental evidence for a complex conformational energy landscape that is explored during receptor activation resulting in signalling. NMR studies have highlighted both the dynamic properties of different receptor states as well as the exchange pathways and intermediates formed during activation, extending the static view of GPCRs obtained from other techniques. NMR studies can be undertaken in realistic membrane-like phospholipid environments and an ever-increasing choice of labelling strategies provides comprehensive, receptor-wide information. Combined with other structural methods, NMR is contributing to our understanding of allosteric signal propagation and the interaction of GPCRs with intracellular binding partners (IBP), crucial to explaining cellular signalling.