Rising Stars: Molecular Mechanisms of Ligand Recognition and Functional Modulation of GPCRs.

In response to a variety of signals outside of cells, G protein-coupled receptors (GPCRs) play essential roles in cell signal transduction by relaying the extracellular signals to the intracellular side through various signaling mechanisms, which govern diverse physiological and pathological processes. These receptors are involved in many diseases and comprise the largest drug target family. However, the molecular mechanisms underlying the GPCR signal transduction are poorly understood, which hinders the drug discovery with only a small portion of receptors having drugs marketed. Over the past decade, our laboratory has been focused on the ligand recognition and functional modulation mechanisms of different GPCRs, aiming for better understanding of the physiology and pathology of this receptor superfamily and new clues to carry out drug development. Through extensive structural and functional studies, we uncovered diverse interaction patterns of GPCRs in recognizing various ligands, including small molecules, peptides, and proteins. These molecular details not only reveal key factors that define ligand selectivity and receptor specificity, but also provide insights into allosteric modulation, ligand promiscuity, and intrinsic activation. Our knowledge about the GPCR modulations were further extended by investigating the conformational rearrangements and dynamics of GPCRs upon activation and coupling to downstream signaling transducers. With different molecular architectures, different receptors exhibit distinct patterns in regulating their activities and abilities to stimulate various signaling pathways, which are key for understanding biased signaling. These findings demonstrate the diversity and complexity of GPCR signaling and would enable development of novel drugs with improved efficacy and reduced side effects.