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TitleStructural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HTR and 5-HTR.
Journal, issue, pagesSci Adv, Vol. 10, Issue 16, Page eadk4855, Year 2024
Publish dateApr 19, 2024
AuthorsGregory Zilberg / Alexandra K Parpounas / Audrey L Warren / Bianca Fiorillo / Davide Provasi / Marta Filizola / Daniel Wacker /
PubMed AbstractSerotonin [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.
External linksSci Adv / PubMed:38630816 / PubMed Central
MethodsEM (single particle)
Resolution3.31 Å
Structure data

42241

8ugy

EMDB-42241, PDB-8ugy:
Serotonin 1E receptor (5-HT1eR)-Gi1 Complex bound with Mianserin
Method: EM (single particle) / Resolution: 3.31 Å

42245

8uh3

EMDB-42245, PDB-8uh3:
Serotonin 1E receptor (5-HT1eR)-Gi1 Complex bound with Setiptiline
Method: EM (single particle) / Resolution: 3.31 Å

Chemicals

ChemComp-CLR:
CHOLESTEROL / Cholesterol


ChemComp, No image

ChemComp-WRU:
Unknown entry

ChemComp-HOH:
WATER / Water


ChemComp, No image

ChemComp-WOQ:
Unknown entry

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsSIGNALING PROTEIN / GPCR / Complex

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