Structure insights into selective coupling of G protein subtypes by a class B G protein-coupled receptor

The ability to couple with multiple G protein subtypes, such as G s , G i/o , or G q/11 , by a given G protein-coupled receptor (GPCR) is critical for many physiological processes. Over the past few years, the cryo-EM structures for all 15 members of the medically important class B GPCRs, all in complex with G s protein, have been determined. However, no structure of class B GPCRs with G q/11 has been solved to date, limiting our understanding of the precise mechanisms of G protein coupling selectivity. Here we report the structures of corticotropin releasing factor receptor 2 (CRF2R) bound to Urocortin 1 (UCN1), coupled with different classes of heterotrimeric G proteins, G 11 and G o . We compare these structures with the structure of CRF2R in complex with G s to uncover the structural differences that determine the selective coupling of G protein subtypes by CRF2R. These results provide important insights into the structural basis for the ability of CRF2R to couple with multiple G protein subtypes.