Structural Insights into Activation and Allosteric Modulation of G Protein-Coupled Receptors

G protein-coupled receptors (GPCRs) are cell-surface receptors that regulate neurotransmission, cardiovascular function, metabolic homeostasis, and many other physiological processes. Due to their central role in human physiology, these receptors are among the most important targets of therapeutic drugs, and are they among the most extensively studied integral membrane proteins. To better understand GPCR signaling at a molecular level, we have undertaken structural studies of a prototypical GPCR family, the muscarinic acetylcholine receptors. These studies have led to crystal structures of muscarinic receptors in both inactive and active conformations, as well as the first structure of a GPCR in complex with a drug-like allosteric modulator. In addition, we have recently developed new approaches in combinatorial biology to create protein modulators of GPCR signaling. These studies shed light on the function of muscarinic receptors, and offer insights into the molecular basis for the regulation of GPCR signaling and activation in general.