8UH3
Serotonin 1E receptor (5-HT1eR)-Gi1 Complex bound with Setiptiline
Summary for 8UH3
| Entry DOI | 10.2210/pdb8uh3/pdb |
| Related | 8UGY |
| EMDB information | 42245 |
| Descriptor | Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(i) subunit alpha-1, 5-hydroxytryptamine receptor 1E, ... (8 entities in total) |
| Functional Keywords | complex, gpcr, signaling protein |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 5 |
| Total formula weight | 159088.23 |
| Authors | Wacker, D.,Parpounas, A.K.,Warren, A.L.,Zilberg, G. (deposition date: 2023-10-06, release date: 2024-05-01, Last modification date: 2024-10-30) |
| 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 Cited by 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: 38630816DOI: 10.1126/sciadv.adk4855 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (3.31 Å) |
Structure validation
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