5-hydroxytryptamine receptor 6
G protein-coupled serotonin receptor activity
GPCRs steer G<sub>i</sub> and G<sub>s</sub> 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<sub>s</sub>, G<sub>i,</sub> or G<sub>q</sub> proteins. The structural basis for G protein subtype selectivity by these GPCRs remains elusive. Here, we report the structures of the serotonin receptors 5-HT<sub>4</sub>, 5-HT<sub>6</sub>, and 5-HT<sub>7</sub> with G<sub>s</sub>, and 5-HT<sub>4</sub> with G<sub>i1</sub>. The structures reveal that transmembrane helices TM5 and TM6 alternate lengths as a macro-switch to determine receptor's selectivity for G<sub>s</sub> and G<sub>i</sub>, 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<sub>s</sub> or G<sub>i</sub>. Together, these results present a common mechanism of G<sub>s</sub> versus G<sub>i</sub> protein coupling selectivity or promiscuity by class A GPCRs and extend the basis of ligand recognition at serotonin receptors.