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Open data
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Basic information
Entry | Database: PDB / ID: 8ugy | |||||||||||||||
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Title | Serotonin 1E receptor (5-HT1eR)-Gi1 Complex bound with Mianserin | |||||||||||||||
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Function / homology | ![]() adenylate cyclase-inhibiting serotonin receptor signaling pathway / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||||||||
Biological species | ![]() ![]() | |||||||||||||||
Method | ![]() ![]() ![]() | |||||||||||||||
![]() | Zilberg, G. / Warren, A.L. / Wacker, D. | |||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural insights into the unexpected agonism of tetracyclic antidepressants at serotonin receptors 5-HTR and 5-HTR. Authors: Gregory Zilberg / Alexandra K Parpounas / Audrey L Warren / Bianca Fiorillo / Davide Provasi / Marta Filizola / Daniel Wacker / ![]() 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. | |||||||||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 173 KB | Display | ![]() |
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PDB format | ![]() | 131.4 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 42241MC ![]() 8uh3C M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#1: Protein | Mass: 40414.047 Da / Num. of mol.: 1 / Mutation: S47N, G203A, E245A, and A326S Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
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#2: Protein | Mass: 39418.086 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
#3: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
-Protein , 1 types, 1 molecules R
#4: Protein | Mass: 38822.594 Da / Num. of mol.: 1 / Mutation: L111W Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
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-Non-polymers , 3 types, 7 molecules ![](data/chem/img/CLR.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/HOH.gif)
#5: Chemical | ChemComp-CLR / ![]() #6: Chemical | ChemComp-WRU / | Mass: 264.365 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H20N2 / Feature type: SUBJECT OF INVESTIGATION #7: Water | ChemComp-HOH / | ![]() |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: ![]() |
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Sample preparation
Component | Name: Quaternary complex of serotonin receptor 5-HT1eR with the Gi1 heterotrimer Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: ![]() ![]() |
Source (recombinant) | Organism: ![]() ![]() ![]() |
Buffer solution | pH: 7.4 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied![]() ![]() |
Vitrification![]() | Instrument: LEICA EM GP / Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source![]() ![]() |
Electron lens | Mode: BRIGHT FIELD![]() |
Image recording | Electron dose: 52.54 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
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CTF correction![]() | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3D reconstruction![]() | Resolution: 3.31 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1321565 / Symmetry type: POINT | ||||||||||||||||||||||||
Refine LS restraints |
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