Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
heterotrimeric G-protein complex
Cryo-EM structure of the serotonin 5-HT&lt;sub&gt;1B&lt;/sub&gt; receptor coupled to heterotrimeric G&lt;sub&gt;o&lt;/sub&gt;.
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<sub>s</sub> to four different GPCRs have been elucidated<sup>1-4</sup>, 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<sub>1B</sub> receptor (5-HT<sub>1B</sub>R) bound to the agonist donitriptan and coupled to an engineered G<sub>o</sub> heterotrimer. In this complex, 5-HT<sub>1B</sub>R is in an active state; the intracellular domain of the receptor is in a similar conformation to that observed for the β<sub>2</sub>-adrenoceptor (β<sub>2</sub>AR) <sup>3</sup> or the adenosine A<sub>2A</sub> receptor (A<sub>2A</sub>R) <sup>1</sup> in complex with G<sub>s</sub>. In contrast to the complexes with G<sub>s</sub>, the gap between the receptor and the Gβ-subunit in the G<sub>o</sub>-5-HT<sub>1B</sub>R complex precludes molecular contacts, and the interface between the Gα-subunit of G<sub>o</sub> 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<sub>o</sub> α-subunit. The molecular variations between the interfaces of G<sub>o</sub> and G<sub>s</sub> in complex with GPCRs may contribute substantially to both the specificity of coupling and the kinetics of signalling.