Activation of G-protein-coupled receptors: a common molecular mechanism

G-protein-coupled receptors (GPCRs) are a large family of proteins that contain a seven transmembrane helical structural motif. They mediate responses to several ligands by binding and activating intracellular heterotrimeric G proteins. Since the cloning of the first GPCR, insights gained from structure‐function studies, genetics and drug development have contributed to uncovering a common mechanism that explains the activation of diverse GPCRs by their cognate agonists. This mechanism takes into consideration the conservation of the structure‐function relationship in the basic seven transmembrane structural motif, and the dynamic changes in receptor conformation that are associated with activation. Combining models derived from the X-ray structure of rhodopsin with structure‐function data allows a deeper understanding of the activation mechanism of GPCRs. The G-protein-coupled receptor (GPCR) superfamily is one of the largest families of proteins in mammals. GPCR signaling is the primary mechanism by which cells sense changes in the external environment and convey this information to their interior. Abnormalities of signaling by GPCRs are at the root of disorders that affect most tissues and organs in our body, such as hyperfunctioning thyroid adenoma, precocious puberty, nephrogenic diabetes insipidus and color blindness. Targeting GPCRs for therapeutic intervention has been fruitful, with .50% of drugs on the market acting as either surrogate activators or inhibitors of the GPCRs that have defined native ligands. However, the majority of GPCRs identified (.75%) are orphan receptors, which presents a challenge for identifying their native ligands and defining their function. The common structural criteria for inclusion in the GPCR superfamily is the presence of seven stretches of 25‐35 predominantly hydrophobic residues that are believed to form a seven transmembrane (7TM) a-helical bundle with helices linked by three intracellular and three