Molecular basis for the selective G protein signaling of somatostatin receptors

G protein-coupled receptors (GPCRs) modulate every aspect of physiological functions mainly through activating heterotrimeric G proteins. A majority of GPCRs promiscuously couple to multiple G protein subtypes. Here we validate that in addition to the well-known Gi/o pathway, somatostatin receptor 2 and 5 (SSTR2 and SSTR5) couple to the Gq/11 pathway and show that smaller ligands preferentially activate the Gi/o pathway. We further determined cryo-electron microscopy structures of the SSTR2‒Go and SSTR2‒Gq complexes bound to octreotide and SST-14. Structural and functional analysis revealed that G protein selectivity of SSTRs is not only determined by structural elements in the receptor–G protein interface, but also by the conformation of the agonist-binding pocket. Accordingly, smaller ligands fail to stabilize a broader agonist-binding pocket of SSTRs that is required for efficient Gq/11 coupling but not Gi/o coupling. Our studies facilitate the design of drugs with selective G protein signaling to improve therapeutic efficacy.