Conformational Signatures of Preassembled and Active Complexes of 5-HT ₇ with the G _s Protein

5-Hydroxytryptamine receptor type 7 (5-HT₇) receptor is a G protein-coupled receptor (GPCR) exhibiting noncanonical signaling properties. It has been shown that 5-HT₇ can form stable inactive preassembled complexes with its cognate G_s protein. Structural determinants of such complex formation and the distinction between preassembled and intermediate activated complexes remain unknown. Here, we use molecular modeling and molecular dynamics simulations to determine and characterize the binding interface between this receptor and the G_s protein in both the active and preassembly complexes. Our results show key interaction patterns specific for the different states and pinpoint unique structural features distinguishing active, inactive, and preassembled states of the receptor.