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- PDB-8fyx: Buspirone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex -
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Open data
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Basic information
Entry | Database: PDB / ID: 8fyx | ||||||||||||||||||
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Title | Buspirone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex | ||||||||||||||||||
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Function / homology | ![]() regulation of serotonin secretion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / dopamine neurotransmitter receptor activity, coupled via Gs / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | ||||||||||||||||||
Biological species | ![]() ![]() | ||||||||||||||||||
Method | ![]() ![]() ![]() | ||||||||||||||||||
![]() | Warren, A.L. / Zilberg, G. / Capper, M.J. / Wacker, D. | ||||||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural pharmacology and therapeutic potential of 5-methoxytryptamines. Authors: Audrey L Warren / David Lankri / Michael J Cunningham / Inis C Serrano / Lyonna F Parise / Andrew C Kruegel / Priscilla Duggan / Gregory Zilberg / Michael J Capper / Vaclav Havel / Scott J ...Authors: Audrey L Warren / David Lankri / Michael J Cunningham / Inis C Serrano / Lyonna F Parise / Andrew C Kruegel / Priscilla Duggan / Gregory Zilberg / Michael J Capper / Vaclav Havel / Scott J Russo / Dalibor Sames / Daniel Wacker / ![]() Abstract: Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their ...Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT (ref. ). However, 5-HT also plays a part in the behavioural effects of tryptamine hallucinogens, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads. Although 5-HT is a validated therapeutic target, little is known about how psychedelics engage 5-HT and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT and 5-HT enable the characterization of molecular determinants of 5-HT signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT agonists. We show that a 5-HT-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders. | ||||||||||||||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 187.2 KB | Display | ![]() |
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PDB format | ![]() | 139.3 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 29599MC ![]() 8fy8C ![]() 8fyeC ![]() 8fylC ![]() 8fytC 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: 4 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 Details: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 with n-terminal his-tag and 3C cleavage site and GSSG linker Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
#3: Protein | Mass: 8506.765 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: 61375.930 Da / Num. of mol.: 1 / Mutation: 3 Source method: isolated from a genetically manipulated source Details: N-terminal HA signal sequence, flag-tag, his-tag, tev cleavage site followed by soluble cytochrome b562 (E. coli) and truncated 5-hydroxytryptamine receptor 1A (Homo sapiens) with a point ...Details: N-terminal HA signal sequence, flag-tag, his-tag, tev cleavage site followed by soluble cytochrome b562 (E. coli) and truncated 5-hydroxytryptamine receptor 1A (Homo sapiens) with a point mutation at position 255 in the provided sequence. This mutation is Ballesteros-Weinstein position 3.41 of 5-HT1A where the original leucine was mutated to a tryptophan. Cytochrome b562 (cybC, UniProt P0ABE7) is both n and c-terminally truncated with two point mutations.,N-terminal HA signal sequence, flag-tag, his-tag, tev cleavage site followed by soluble cytochrome b562 (E. coli) and truncated 5-hydroxytryptamine receptor 1A (Homo sapiens) with a point mutation at position 255 in the provided sequence. This mutation is Ballesteros-Weinstein position 3.41 of 5-HT1A where the original leucine was mutated to a tryptophan. Cytochrome b562 (cybC, UniProt P0ABE7) is both n and c-terminally truncated with two point mutations. Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
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-Non-polymers , 3 types, 4 molecules ![](data/chem/img/J40.gif)
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#5: Chemical | ChemComp-YLX / Mass: 385.503 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H31N5O2 / Feature type: SUBJECT OF INVESTIGATION |
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#6: Chemical | ChemComp-J40 / [( |
#7: Chemical |
-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: Serotonin 1A (5-HT1A) receptor-Gi1 protein complex / Type: COMPLEX Details: Serotonin 1A (5-HT1A) receptor-Gi1 protein complex with components purified separately and assembled in vitro. Entity ID: #1-#4 / Source: RECOMBINANT | ||||||||||||||||||||||||
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Molecular weight | Experimental value: NO | ||||||||||||||||||||||||
Source (natural) | Organism: Escherichia coli, Homo sapiens | ||||||||||||||||||||||||
Source (recombinant) | Organism: ![]() ![]() ![]() ![]() | ||||||||||||||||||||||||
Buffer solution | pH: 7.4 | ||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 24 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied![]() ![]() Details: Sample was mono disperse following gel filtration. The sample was immediately concentrated for CryoEM grid preparation. | ||||||||||||||||||||||||
Specimen support | Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil | ||||||||||||||||||||||||
Vitrification![]() | Instrument: LEICA EM GP / Cryogen name: ETHANE Details: Blot force 3 for 3-5 seconds was used and subsequent grids were screened for ice thickness prior to data collection. |
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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: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
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Processing
EM software |
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CTF correction![]() | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||||||||
Particle selection | Num. of particles selected: 4167166 | |||||||||||||||||||||||||||||||||
3D reconstruction![]() | Resolution: 2.62 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 586489 Details: NU refinement performed in cryoSPARC. Resolution value provided is from refinement with a tight mask. Num. of class averages: 1 / Symmetry type: POINT |