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- PDB-6wha: HTR2A bound to 25-CN-NBOH in complex with a mini-Galpha-q protein... -
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Open data
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Basic information
Entry | Database: PDB / ID: 6wha | |||||||||
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Title | HTR2A bound to 25-CN-NBOH in complex with a mini-Galpha-q protein, beta/gamma subunits and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM) | |||||||||
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Function / homology | ![]() protein localization to cytoskeleton / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / phospholipase C-activating serotonin receptor signaling pathway / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / artery smooth muscle contraction / serotonin receptor signaling pathway / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | |||||||||
Method | ![]() ![]() ![]() | |||||||||
![]() | Skiniotis, G. / Roth, B. / Kim, K. / Panova, O. | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Structure of a Hallucinogen-Activated Gq-Coupled 5-HT Serotonin Receptor. Authors: Kuglae Kim / Tao Che / Ouliana Panova / Jeffrey F DiBerto / Jiankun Lyu / Brian E Krumm / Daniel Wacker / Michael J Robertson / Alpay B Seven / David E Nichols / Brian K Shoichet / Georgios ...Authors: Kuglae Kim / Tao Che / Ouliana Panova / Jeffrey F DiBerto / Jiankun Lyu / Brian E Krumm / Daniel Wacker / Michael J Robertson / Alpay B Seven / David E Nichols / Brian K Shoichet / Georgios Skiniotis / Bryan L Roth / ![]() Abstract: Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many ...Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders. | |||||||||
History |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 197.8 KB | Display | ![]() |
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PDB format | ![]() | 152.4 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 21669MC M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Protein , 2 types, 2 molecules AB
#1: Protein | Mass: 56167.309 Da / Num. of mol.: 1 Fragment: cybC (UNP residues 23-127) + linker + HTR2A (UNP residues 66-404) Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() Gene: cybC, HTR2A, HTR2 / Production host: ![]() ![]() ![]() |
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#2: Protein | Mass: 28084.832 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
-Guanine nucleotide-binding protein ... , 2 types, 2 molecules CD
#3: Protein | Mass: 39418.086 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
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#4: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
-Antibody / Non-polymers , 2 types, 2 molecules E![](data/chem/img/U0G.gif)
![](data/chem/img/U0G.gif)
#5: Antibody | Mass: 28668.922 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() ![]() |
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#6: Chemical | ChemComp-U0G / ![]() |
-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: HTR2A bound to 25-CN-NBOH in complex with a mini-Galpha-q protein, beta/gamma subunits and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM) Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT | ||||||||||||||||||||||||||||||||||||
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Source (natural) | Organism: ![]() ![]() | ||||||||||||||||||||||||||||||||||||
Source (recombinant) | Organism: ![]() ![]() ![]() | ||||||||||||||||||||||||||||||||||||
Buffer solution | pH: 7.5 | ||||||||||||||||||||||||||||||||||||
Buffer component |
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Specimen | Conc.: 16.7 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied![]() ![]() | ||||||||||||||||||||||||||||||||||||
Specimen support | Grid material: GOLD / Grid type: Quantifoil R1.2/1.3 | ||||||||||||||||||||||||||||||||||||
Vitrification![]() | Instrument: FEI VITROBOT MARK II / 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![]() ![]() |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average exposure time: 4 sec. / Electron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 2368 |
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Processing
Software | Name: PHENIX / Version: 1.17.1_3660: / Classification: refinement | ||||||||||||||||||||||||
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EM software |
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CTF correction![]() | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Particle selection | Num. of particles selected: 2712613 | ||||||||||||||||||||||||
Symmetry | Point symmetry![]() | ||||||||||||||||||||||||
3D reconstruction![]() | Resolution: 3.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 166497 / Num. of class averages: 1 / Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 59.95 Å2 | ||||||||||||||||||||||||
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