5-hydroxytryptamine receptor 1E
adenylate cyclase-inhibiting serotonin receptor signaling pathway
Structural insights into the ligand binding and G<sub>i</sub> coupling of serotonin receptor 5-HT<sub>5A</sub>.
5-hydroxytryptamine receptor 5A (5-HT<sub>5A</sub>) belongs to the 5-HT receptor family and signals through the G<sub>i/o</sub> protein. It is involved in nervous system regulation and an attractive target for the treatment of psychosis, depression, schizophrenia, and neuropathic pain. 5-HT<sub>5A</sub> is the only G<sub>i/o</sub>-coupled 5-HT receptor subtype lacking a high-resolution structure, which hampers the mechanistic understanding of ligand binding and G<sub>i/o</sub> coupling for 5-HT<sub>5A</sub>. Here we report a cryo-electron microscopy structure of the 5-HT<sub>5A</sub>-G<sub>i</sub> complex bound to 5-Carboxamidotryptamine (5-CT). Combined with functional analysis, this structure reveals the 5-CT recognition mechanism and identifies the receptor residue at 6.55 as a determinant of the 5-CT selectivity for G<sub>i/o</sub>-coupled 5-HT receptors. In addition, 5-HT<sub>5A</sub> shows an overall conserved G<sub>i</sub> protein coupling mode compared with other G<sub>i/o</sub>-coupled 5-HT receptors. These findings provide comprehensive insights into the ligand binding and G protein coupling of G<sub>i/o</sub>-coupled 5-HT receptors and offer a template for the design of 5-HT<sub>5A</sub>-selective drugs.