摘要GPR20,an orphan G protein-coupled receptor(GPCR),shows significant expression in intestinal tissue and represents a potential therapeutic target to treat gastrointestinal stromal tumors.GPR20 performs high constitutive activity when coupling with Gi.Despite the pharmacological importance of GPCR constitutive activation,determining the mechanism has long remained unclear.In this study,we explored the constitutive activation mechanism of GPR20 through large-scale unbiased molecular dynamics simulations.Our results unveil the allosteric nature of constitutively activated GPCR signal transduction involving extracellular and intracellular domains.Moreover,the constitutively active state of the GPR20 requires both the N-terminal cap and Gi protein.The N-terminal cap of GPR20 functions like an agonist and mediates long-range activated conformational shift.Together with the previous study,this study enhances our knowledge of the self-activation mechanism of the orphan receptor,facilitates the drug discovery efforts that target GPR20.