8UGY

Serotonin 1E receptor (5-HT1eR)-Gi1 Complex bound with Mianserin

Summary for 8UGY

• Entry DOI: 10.2210/pdb8ugy/pdb
• EMDB information: 42241
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: gpcr, signaling protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 128713.51

Authors

Zilberg, G.,Warren, A.L.,Wacker, D. (deposition date: 2023-10-06, release date: 2024-05-01, Last modification date: 2024-10-23)

Primary citation

Zilberg, G.,Parpounas, A.K.,Warren, A.L.,Fiorillo, B.,Provasi, D.,Filizola, M.,Wacker, D.
Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HT 1e R and 5-HT 1F R.
Sci Adv, 10:eadk4855-eadk4855, 2024

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. 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.

PubMed: 38630816
DOI: 10.1126/sciadv.adk4855

Experimental method

ELECTRON MICROSCOPY (3.31 Å)