GPCRs steer Gi and Gs selectivity via TM5-TM6 switches as revealed by structures of serotonin receptors

Serotonin (or 5-hydroxytryptamine, 5-HT) is an important neurotransmitter that activates 12 different G protein-coupled receptors (GPCRs) through selective coupling of G(s), G(i), or G(q) proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT4, 5-HT6, and 5-HT7 with G(s), and 5-HT4 with G(i1). The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for G(s) and G(i), respectively. We find that the macro-switch by the TM5-TM6 length is shared by class A GPCR-G protein structures. Furthermore, we discover specific residues within TM5 and TM6 that function as micro-switches to form specific interactions with G(s) or G(i). Together, these results present a common mechanism of G(s) versus G(i) protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors.

Automated summary

This study reveals the mechanism of selectivity in coupling between serotonin receptors and G proteins. It is found that the length of TM5 and TM6 can act as a macro-switch to determine the receptor's preference for G(s) or G(i) proteins. Additionally, specific residues within TM5 and TM6 function as micro-switches to form specific interactions with G(s) or G(i). These findings extend our understanding of ligand recognition at serotonin receptors.