NMR Spectroscopy for the Characterization of GPCR Energy Landscapes

G protein-coupled receptor (GPCR)-mediated signal transduction has a central role in human physiology and implication in many diseases. Despite the tremendous number of X-ray crystallography structures published in the past decade, the molecular mechanisms of ligand-dependent signaling remain to be completed. In particular, very little information is available concerning the implication of receptor dynamics and conformational changes on GPCR ligand efficiency and coupling. In this context, mapping the conformational landscape of GPCRs, and how it is modulated by the membrane environment and allosteric and signaling partners, is fundamental in order to gain a clear picture of how the signaling mechanism proceeds. Solution-state nuclear magnetic resonance (NMR) is a powerful technique to study GPCR energy landscapes, i.e., conformational ensembles along activation and inactivation pathway, and associated kinetic barriers.