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Title | Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HTR and 5-HTR. |
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Journal, issue, pages | Sci Adv, Vol. 10, Issue 16, Page eadk4855, Year 2024 |
Publish date | Apr 19, 2024 |
![]() | Gregory Zilberg / Alexandra K Parpounas / Audrey L Warren / Bianca Fiorillo / Davide Provasi / Marta Filizola / Daniel Wacker / ![]() |
PubMed Abstract | Serotonin [5-hydroxytryptamine (5-HT)] acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HTR have confirmed roles in native tissue and are validated drug targets. ...Serotonin [5-hydroxytryptamine (5-HT)] acts via 13 different receptors in humans. Of these receptor subtypes, all but 5-HTR have confirmed roles in native tissue and are validated drug targets. Despite 5-HTR's therapeutic potential and plausible druggability, the mechanisms of its activation remain elusive. To illuminate 5-HTR's pharmacology in relation to the highly homologous 5-HTR, we screened a library of aminergic receptor ligands at both receptors and observe 5-HTR/5-HTR 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-HTR 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-HTR and 5-HTR contribute to the agonist activity of these antidepressants. |
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Methods | EM (single particle) |
Resolution | 3.31 Å |
Structure data | EMDB-42241, PDB-8ugy: EMDB-42245, PDB-8uh3: |
Chemicals | ![]() ChemComp-CLR: ![]()
ChemComp-WRU: ![]() ChemComp-HOH: ![]()
ChemComp-WOQ: |
Source |
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