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 alpha-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-HT1B receptor (5-HT1BR) bound to the agonist donitriptan and coupled to an engineered Go heterotrimer. In this complex, 5-HT1BR is in an active state; the intracellular domain of the receptor is in a similar conformation to that observed for the beta(2)-adrenoceptor (beta(2)AR)(3) or the adenosine A(2A) receptor (A(2A)R)(1) in complex with Gs. In contrast to the complexes with G(s), the gap between the receptor and the G beta-subunit in the G(o)-5-HT1BR complex precludes molecular contacts, and the interface between the G alpha-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) alpha-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.