Membrane proteins play fundamental roles in many physiological processes and also are target proteins for drug development. However, it is frequently difficult to obtain structural information about the membrane protein dynamics related to the functions. This is mainly due to the difficulties in sample preparation: expression and purification of the membrane proteins with the biological activities, and lack of appropriate NMR strategy. In this paper, we will show our recent results of dynamical aspects of G-protein coupled receptors (GPCR), which are responsible for the biological functions
Many drugs that target GPCRs induce or inhibit signal transduction with different strengths, which affect their therapeutic properties. However, the signal transduction mechanism of GPCR is still not clear, although several structures of GPCRs with ligands determined by X-ray crystallography are available. Here we utilized NMR to monitor the signals from the methionine residue at position 82 of2-adrenergic receptor (2AR). We show that this residue exists in a conformational equilibrium between the inverse agonist-bound states and the full agonist-bound state, and the population of the latter reflects the signal transduction level in each ligand-bound state. These functional equilibriums provide insights into the multi-level signaling of 2AR and other GPCRs, including the basal activity, and the mechanism of signal transduction mediated by GPCRs.