8uh3
Serotonin 1E receptor (5-HT1eR)-Gi1 Complex bound with Setiptiline
Structural highlights
FunctionGBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction.[1] Publication Abstract from PubMedSerotonin [5-hydroxytryptamine (5-HT)] acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HT(1e)R have confirmed roles in native tissue and are validated drug targets. Despite 5-HT(1e)R's therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HT(1e)R's pharmacology in relation to the highly homologous 5-HT(1F)R, we screened a library of aminergic receptor ligands at both receptors and observe 5-HT(1e)R/5-HT(1F)R agonism by multicyclic drugs described as pan-antagonists at 5-HT receptors. Potent agonism by tetracyclic antidepressants mianserin, setiptiline, and mirtazapine suggests a mechanism for their clinically observed antimigraine properties. Using cryo-EM and mutagenesis studies, we uncover and characterize unique agonist-like binding poses of mianserin and setiptiline at 5-HT(1e)R distinct from similar drug scaffolds in inactive-state 5-HTR structures. Together with computational studies, our data suggest that these binding poses alongside receptor-specific allosteric coupling in 5-HT(1e)R and 5-HT(1F)R contribute to the agonist activity of these antidepressants. Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT(1e)R and 5-HT(1F)R.,Zilberg G, Parpounas AK, Warren AL, Fiorillo B, Provasi D, Filizola M, Wacker D Sci Adv. 2024 Apr 19;10(16):eadk4855. doi: 10.1126/sciadv.adk4855. Epub 2024 Apr , 17. PMID:38630816[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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