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- EMDB-0282: CryoEM structure of human full-length heteromeric alpha1beta3gamm... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-0282 | |||||||||||||||||||||||||||
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Title | CryoEM structure of human full-length heteromeric alpha1beta3gamma2L GABA(A)R in complex with alprazolam (Xanax), GABA and megabody Mb38. | |||||||||||||||||||||||||||
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![]() | GABAAR / ![]() ![]() | |||||||||||||||||||||||||||
Function / homology | ![]() GABA receptor activation / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||||||||||||||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | |||||||||||||||||||||||||||
Method | ![]() ![]() | |||||||||||||||||||||||||||
![]() | Masiulis S / Desai R | |||||||||||||||||||||||||||
Funding support | ![]() ![]() ![]()
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![]() | ![]() Title: GABA receptor signalling mechanisms revealed by structural pharmacology. Authors: Simonas Masiulis / Rooma Desai / Tomasz Uchański / Itziar Serna Martin / Duncan Laverty / Dimple Karia / Tomas Malinauskas / Jasenko Zivanov / Els Pardon / Abhay Kotecha / Jan Steyaert / ...Authors: Simonas Masiulis / Rooma Desai / Tomasz Uchański / Itziar Serna Martin / Duncan Laverty / Dimple Karia / Tomas Malinauskas / Jasenko Zivanov / Els Pardon / Abhay Kotecha / Jan Steyaert / Keith W Miller / A Radu Aricescu / ![]() ![]() ![]() ![]() Abstract: Type-A γ-aminobutyric (GABA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the ...Type-A γ-aminobutyric (GABA) receptors are ligand-gated chloride channels with a very rich pharmacology. Some of their modulators, including benzodiazepines and general anaesthetics, are among the most successful drugs in clinical use and are common substances of abuse. Without reliable structural data, the mechanistic basis for the pharmacological modulation of GABA receptors remains largely unknown. Here we report several high-resolution cryo-electron microscopy structures in which the full-length human α1β3γ2L GABA receptor in lipid nanodiscs is bound to the channel-blocker picrotoxin, the competitive antagonist bicuculline, the agonist GABA (γ-aminobutyric acid), and the classical benzodiazepines alprazolam and diazepam. We describe the binding modes and mechanistic effects of these ligands, the closed and desensitized states of the GABA receptor gating cycle, and the basis for allosteric coupling between the extracellular, agonist-binding region and the transmembrane, pore-forming region. This work provides a structural framework in which to integrate previous physiology and pharmacology research and a rational basis for the development of GABA receptor modulators. | |||||||||||||||||||||||||||
History |
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Structure visualization
Movie |
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 5.3 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 28 KB 28 KB | Display Display | ![]() |
Images | ![]() | 173.8 KB | ||
Filedesc metadata | ![]() | 8.3 KB | ||
Others | ![]() ![]() ![]() | 49.5 MB 49.9 MB 49.9 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 6huoMC ![]() 0275C ![]() 0279C ![]() 0280C ![]() 0283C ![]() 6hugC ![]() 6hujC ![]() 6hukC ![]() 6hupC M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 1.07 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Additional map: Unsharpened map
File | emd_0282_additional.map | ||||||||||||
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Annotation | Unsharpened map | ||||||||||||
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Density Histograms |
-Half map: Half-map 2
File | emd_0282_half_map_1.map | ||||||||||||
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Annotation | Half-map 2 | ||||||||||||
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Density Histograms |
-Half map: Half-map 1
File | emd_0282_half_map_2.map | ||||||||||||
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Annotation | Half-map 1 | ||||||||||||
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Sample components
+Entire : CryoEM structure of human full-length heteromeric alpha1beta3gamm...
+Supramolecule #1: CryoEM structure of human full-length heteromeric alpha1beta3gamm...
+Supramolecule #2: heteromeric alpha1beta3gamma2L GABA(A)R
+Supramolecule #3: megabody Mb38
+Macromolecule #1: Gamma-aminobutyric acid receptor subunit alpha-1,Gamma-aminobutyr...
+Macromolecule #2: Gamma-aminobutyric acid receptor subunit beta-3
+Macromolecule #3: Gamma-aminobutyric acid receptor subunit gamma-2
+Macromolecule #4: Megabody Mb38
+Macromolecule #9: GAMMA-AMINO-BUTANOIC ACID
+Macromolecule #10: [(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(o...
+Macromolecule #11: 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodia...
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Concentration | 0.1 mg/mL |
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Buffer | pH: 7.6 |
Vitrification | Cryogen name: ETHANE / Instrument: FEI VITROBOT MARK IV |
Details | Monodisperse sample |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Specialist optics | Phase plate: VOLTA PHASE PLATE |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Image recording | Film or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Average electron dose: 30.0 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Particle selection | Number selected: 210073 |
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Startup model | Type of model: OTHER / Details: Relion 3D ab-initio |
Initial angle assignment | Type: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.0) / Software - details: Refine3D |
Final 3D classification | Software - Name: RELION (ver. 3.0) / Software - details: Class3D |
Final angle assignment | Type: ANGULAR RECONSTITUTION / Software - Name: RELION (ver. 3.0) / Software - details: Refine3D |
Final reconstruction | Applied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 3.0) / Software - details: Refine3D / Number images used: 39050 |
-Atomic model buiding 1
Refinement | Space: REAL / Protocol: FLEXIBLE FIT |
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Output model | ![]() PDB-6huo: |