Cryo-EM structure of the serotonin 5-HT1B receptor coupled to heterotrimeric Go

Javier García-Nafría, Rony Nehmé, Patricia C. Edwards and Christopher G. Tate ()
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Javier García-Nafría: MRC Laboratory of Molecular Biology
Rony Nehmé: MRC Laboratory of Molecular Biology
Patricia C. Edwards: MRC Laboratory of Molecular Biology
Christopher G. Tate: MRC Laboratory of Molecular Biology

Nature, 2018, vol. 558, issue 7711, 620-623

Abstract: 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 Gs to four different GPCRs have been elucidated1–4, 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 β2-adrenoceptor (β2AR)3 or the adenosine A2A receptor (A2AR)1 in complex with Gs. In contrast to the complexes with Gs, the gap between the receptor and the Gβ-subunit in the Go–5-HT1BR complex precludes molecular contacts, and the interface between the Gα-subunit of Go 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 Go α-subunit. The molecular variations between the interfaces of Go and Gs in complex with GPCRs may contribute substantially to both the specificity of coupling and the kinetics of signalling.

Date: 2018
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DOI: 10.1038/s41586-018-0241-9

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