痛苦
变构调节
受体
药理学
可药性
变构调节剂
5-羟色胺受体
兴奋剂
米安色林
血清素
功能选择性
G蛋白偶联受体
化学
生物
生物化学
基因
政治
法学
政治学
作者
Gregory Zilberg,Alexandra Kalia Parpounas,Audrey L. Warren,Bianca Fiorillo,Davide Provasi,Marta Filizola,Daniel Wacker
标识
DOI:10.1101/2023.10.05.561100
摘要
Abstract Serotonin (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/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 anti-migraine properties. Using cryoEM 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.
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