Dynamical Basis of GPCR-G Protein Coupling Selectivity and Promiscuity

Agonist bound G-protein-coupled receptors (GPCRs) get activated and couple either selectively or promiscuously to one or multiple members of the G-proteins in the cell. The challenge in designing ligands that are signaling pathway specific (also known as biased or selective ligands) is to uncover the mechanism by which GPCRs couple to different G proteins. The structural dynamics of the GPCR:G protein complexes and the spatiotemporal determinants of the interface play an important role in understanding the determinants of the selectivity or promiscuous coupling. In this chapter we provide an overview of the current understanding of GPCR:G protein selectivity determinants from both kinetic and thermodynamic aspects of the coupling process. Using a confluence of spectroscopic techniques and molecular dynamics simulations we show that GPCRs exhibits a high degree of structural plasticity characterized by latent G-protein binding cavities, each of which is specific for coupling a distinct G-protein.