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As the most known therapeutic component of bear bile acids, ursodeoxycholic acid (UDCA) is an FDA-approved drug for the treatment of primary biliary cirrhosis (PBC), the dissolution of cholesterol gallstones. UDCA produces many beneficial effects on metabolism and immune responses via its interaction with the membrane G protein-coupled bile acid receptor (GPBAR); however, how UDCA interacts with GPBAR and its selective cellular effects remain elusive. In this study, we delineated the interaction of UDCA with GPBAR and activation mechanism of GPBAR by scattered alanine scanning and molecular docking. Our results indicated that transmembrane helix 2 (TM2), TM3, TM5 and TM6 of GPBAR contribute to the interaction of UDCA in GPBAR binding pocket. Moreover, we predicted that the engagement of the 3-OH of UDCA with phenolic oxygen of Y2406.51 in GPBAR plays a key role in GPBAR activation. Unexpectedly, in addition to the well-known roles of intracellular loop2 (ICL2) residues, we identified that ICL3 residues play an important role in G protein coupling to GPBAR in response to UDCA binding. Our study provides a preliminary molecular mechanism of how GPBAR recognizes UDCA and subsequent activation and G protein interaction, which may facilitate the development of new bile acid derivatives as therapeutics. • The scattered alanine scanning method was used to delineate the molecular mechanism of GPBAR activation by UDCA. • TM2, TM3, TM5 and TM6 were identified make contributions in the formation of the binding pocket of UDCA in GPBAR. • UDCA 3-OH and Y2406.51 phenolic oxygen is involved in polar network keeping GPBAR in inactive state in absence of agonist UDCA 3-OH and Y240. phenolic oxygen is involved in polar network keeping GPBAR in inactive state in absence of agonist; • The ICL3 residues are important in G protein coupling by GPBAR in addition to the well-known roles of ICL2 residues. [ABSTRACT FROM AUTHOR]