The endothelin receptor type B (ET) exhibits promiscuous coupling with various heterotrimeric G protein subtypes including Gs, Gi/o, Gq/11, and G12/13. Recent fluorescence and structural studies have raised questions regarding the coupling efficiencies and determinants of these G protein subtypes. Herein, by utilizing an integrative approach, combining hydrogen/deuterium exchange mass spectrometry and NanoLuc Binary Technology-based cellular systems, we investigated conformational changes of Gs, Gi, and Gq triggered by ET activation. ET coupled to Gi and Gq but not with Gs. We underscored the critical roles of specific regions, including the C terminus of Gα and intracellular loop 2 (ICL2) of ET in ET-Gi1 or ET-Gq coupling. Although The C terminus of Gα is essential for ET-Gi1 and ET-Gq coupling, ET ICL2 influences Gq-coupling but not Gi1-coupling. Our results suggest a differential coupling efficiency of ET with Gs, Gi1, and Gq, accompanied by distinct conformational changes in G proteins upon ET-induced activation.
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