Cryo-EM structure of the serotonin 5-HT_1B receptor coupled to heterotrimeric G_o.

Abstract

G-protein-coupled receptors (GPCRs) form the largest family of receptors encoded by the human genome (around 800 genes). They transduce signals by coupling to a small number of heterotrimeric G proteins (16 genes encoding different α-subunits). Each human cell contains several GPCRs and G proteins. The structural determinants of coupling of G_s to four different GPCRs have been elucidated^1-4, but the molecular details of how the other G-protein classes couple to GPCRs are unknown. Here we present the cryo-electron microscopy structure of the serotonin 5-HT_1B receptor (5-HT_1BR) bound to the agonist donitriptan and coupled to an engineered G_o heterotrimer. In this complex, 5-HT_1BR is in an active state; the intracellular domain of the receptor is in a similar conformation to that observed for the β₂-adrenoceptor (β₂AR) ³ or the adenosine A_2A receptor (A_2AR) ¹ in complex with G_s. In contrast to the complexes with G_s, the gap between the receptor and the Gβ-subunit in the G_o-5-HT_1BR complex precludes molecular contacts, and the interface between the Gα-subunit of G_o and the receptor is considerably smaller. These differences are likely to be caused by the differences in the interactions with the C terminus of the G_o α-subunit. The molecular variations between the interfaces of G_o and G_s in complex with GPCRs may contribute substantially to both the specificity of coupling and the kinetics of signalling.