Constitutively active orphan G protein-coupled receptors through the lenses of cryo-electron microscopy

G protein-coupled receptors (GPCRs) are a therapeutically privileged family of receptors involved in a wide variety of pathophysiological conditions and the successful target for ∼34% of FDA-approved drugs. However, a significant percentage of GPCRs remain orphan, i.e., the endogenous ligands that modulate receptor function are unknown, and hence knowledge about their functional role and the generation of new therapeutics lag behind. During recent years, the use of cryo-electron microscopy has revolutionized GPCR structural biology including its application to orphan GPCRs, especially those displaying constitutive activity in cellular model systems. Such efforts have resulted in the description of new modes of in-built agonists that include the ECL2 and N-terminal regions as well as identifying ubiquitous endogenous ligands readily bound to GPCRs. These results position structural determination as a new key component in GPCR deorphanization, shedding light on new signaling mechanisms, bringing questions about their functional regulation, and opening new avenues for drug design.