Structural determinants of G protein subtype selectivity at the serotonin receptor 5-HT1A

Sci Adv. 2025 Aug;11(31):eadu9851. doi: 10.1126/sciadv.adu9851. Epub 2025 Aug 1.

ABSTRACT

Activation of the serotonin receptor 5-HT1A has been shown to regulate mood and cognition, making 5-HT1A an important target in the treatment of anxiety, depression, and psychosis. Although the receptor signals through inhibitory G proteins, more work is necessary to understand differences in transducer coupling and its relation to functional activity. To develop a molecular understanding of the differences underlying transducer coupling and activation, we performed structure-activity relationship studies of 5-HT1A with distinct G proteins. Through a combination of in vitro assays, we identified a potent partial agonist that selectively engages a G protein subtype. We further investigated the differences in G protein engagement at 5-HT1A with cryo-electron microscopy, determining structures of 5-HT1A bound to distinct ligands and G protein subtypes. Combined with subsequent structure-guided mutagenesis and signaling assays, our studies uncover both orthosteric and allosteric determinants of agonist-specific stimulation of distinct transducers.

PMID:40749070 | DOI:10.1126/sciadv.adu9851