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- EMDB-17108: CryoEM structure of human rho1 GABAA receptor in complex with por... -

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Basic information

Entry
Database: EMDB / ID: EMD-17108
TitleCryoEM structure of human rho1 GABAA receptor in complex with pore blocker picrotoxin
Map data
Sample
  • Complex: rho1 GABAA receptor
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit rho-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: HEXANE
  • Ligand: DODECANE
  • Ligand: DECANE
  • Ligand: (1aR,2aR,3S,6R,6aS,8aS,8bR,9R)-2a-hydroxy-8b-methyl-9-(prop-1-en-2-yl)hexahydro-3,6-methano-1,5,7-trioxacyclopenta[ij]c yclopropa[a]azulene-4,8(3H)-dione
  • Ligand: water
KeywordsGABAA receptor / MEMBRANE PROTEIN
Function / homology
Function and homology information


GABA receptor activation / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / gamma-aminobutyric acid signaling pathway / neurotransmitter receptor activity / chloride channel complex / transmembrane transporter complex / GABA-ergic synapse / chloride transmembrane transport ...GABA receptor activation / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / gamma-aminobutyric acid signaling pathway / neurotransmitter receptor activity / chloride channel complex / transmembrane transporter complex / GABA-ergic synapse / chloride transmembrane transport / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / modulation of chemical synaptic transmission / presynaptic membrane / chemical synaptic transmission / postsynaptic membrane / neuron projection / protein domain specific binding / glutamatergic synapse / synapse / protein-containing complex binding / identical protein binding / plasma membrane
Similarity search - Function
Gamma-aminobutyric-acid A receptor, Rho / Gamma-aminobutyric-acid A receptor, Rho1 / Gamma-aminobutyric acid A receptor/Glycine receptor alpha / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / Neurotransmitter-gated ion-channel ...Gamma-aminobutyric-acid A receptor, Rho / Gamma-aminobutyric-acid A receptor, Rho1 / Gamma-aminobutyric acid A receptor/Glycine receptor alpha / Neurotransmitter-gated ion-channel, conserved site / Neurotransmitter-gated ion-channels signature. / Neurotransmitter-gated ion-channel transmembrane domain / Neurotransmitter-gated ion-channel transmembrane region / Neurotransmitter-gated ion-channel transmembrane domain superfamily / Neuronal acetylcholine receptor / Neurotransmitter-gated ion-channel / Neurotransmitter-gated ion-channel ligand-binding domain / Neurotransmitter-gated ion-channel ligand-binding domain superfamily / Neurotransmitter-gated ion-channel ligand binding domain
Similarity search - Domain/homology
Gamma-aminobutyric acid receptor subunit rho-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsChen F / Victor T / John C / Rebecca JH / Erik L
Funding support Sweden, 1 items
OrganizationGrant numberCountry
Swedish Research Council Sweden
CitationJournal: Neuron / Year: 2023
Title: Structure and dynamics of differential ligand binding in the human ρ-type GABA receptor.
Authors: John Cowgill / Chen Fan / Nandan Haloi / Victor Tobiasson / Yuxuan Zhuang / Rebecca J Howard / Erik Lindahl /
Abstract: The neurotransmitter γ-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABARs). Pharmacological properties of ...The neurotransmitter γ-aminobutyric acid (GABA) drives critical inhibitory processes in and beyond the nervous system, partly via ionotropic type-A receptors (GABARs). Pharmacological properties of ρ-type GABARs are particularly distinctive, yet the structural basis for their specialization remains unclear. Here, we present cryo-EM structures of a lipid-embedded human ρ1 GABAR, including a partial intracellular domain, under apo, inhibited, and desensitized conditions. An apparent resting state, determined first in the absence of modulators, was recapitulated with the specific inhibitor (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid and blocker picrotoxin and provided a rationale for bicuculline insensitivity. Comparative structures, mutant recordings, and molecular simulations with and without GABA further explained the sensitized but slower activation of ρ1 relative to canonical subtypes. Combining GABA with picrotoxin also captured an apparent uncoupled intermediate state. This work reveals structural mechanisms of gating and modulation with applications to ρ-specific pharmaceutical design and to our biophysical understanding of ligand-gated ion channels.
History
DepositionApr 11, 2023-
Header (metadata) releaseAug 30, 2023-
Map releaseAug 30, 2023-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_17108.png

Downloads & links

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Map

FileDownload / File: emd_17108.map.gz / Format: CCP4 / Size: 282.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.67 Å/pix.
x 420 pix.
= 282.45 Å		0.67 Å/pix.
x 420 pix.
= 282.45 Å		0.67 Å/pix.
x 420 pix.
= 282.45 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.6725 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.005
Minimum - Maximum-0.01995236 - 0.028882988
Average (Standard dev.)0.000006680862 (±0.00078623067)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions420420420
Spacing420420420
CellA=B=C: 282.45 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_17108_half_map_1.map
Projections & Slices
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Slices (1/2)
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Half map: #1

Fileemd_17108_half_map_2.map
Projections & Slices
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Sample components

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Entire : rho1 GABAA receptor

EntireName: rho1 GABAA receptor
Components
  • Complex: rho1 GABAA receptor
    • Protein or peptide: Gamma-aminobutyric acid receptor subunit rho-1
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: HEXANE
  • Ligand: DODECANE
  • Ligand: DECANE
  • Ligand: (1aR,2aR,3S,6R,6aS,8aS,8bR,9R)-2a-hydroxy-8b-methyl-9-(prop-1-en-2-yl)hexahydro-3,6-methano-1,5,7-trioxacyclopenta[ij]c yclopropa[a]azulene-4,8(3H)-dione
  • Ligand: water

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Supramolecule #1: rho1 GABAA receptor

SupramoleculeName: rho1 GABAA receptor / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Gamma-aminobutyric acid receptor subunit rho-1

MacromoleculeName: Gamma-aminobutyric acid receptor subunit rho-1 / type: protein_or_peptide / ID: 1 / Number of copies: 5 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 55.95023 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MLAVPNMRFG IFLLWWGWVL ATESRMHWPG REVHEMSKKG RPQRQRREVH EDAHKQVSPI LRRSPDITKS PLTKSEQLLR IDDHDFSMR PGFGGPAIPV GVDVQVESLD SISEVDMDFT MTLYLRHYWK DERLSFPSTN NLSMTFDGRL VKKIWVPDMF F VHSKRSFI ...String:
MLAVPNMRFG IFLLWWGWVL ATESRMHWPG REVHEMSKKG RPQRQRREVH EDAHKQVSPI LRRSPDITKS PLTKSEQLLR IDDHDFSMR PGFGGPAIPV GVDVQVESLD SISEVDMDFT MTLYLRHYWK DERLSFPSTN NLSMTFDGRL VKKIWVPDMF F VHSKRSFI HDTTTDNVML RVQPDGKVLY SLRVTVTAMC NMDFSRFPLD TQTCSLEIES YAYTEDDLML YWKKGNDSLK TD ERISLSQ FLIQEFHTTT KLAFYSSTGW YNRLYINFTL RRHIFFFLLQ TYFPATLMVM LSWVSFWIDR RAVPARVPLG ITT VLTMST IITGVNASMP RVSYIKAVDI YLWVSFVFVF LSVLEYAAVN YLTTVQERKE QKLREKLPCT SGLPPPRTAM LDGN YSDGE VNDLDNYMPE NGEKPDRMMV QLTLASERSS PQRKSQRSSY VSMRIDTHAI DKYSRIIFPA AYILFNLIYW SIFS

UniProtKB: Gamma-aminobutyric acid receptor subunit rho-1

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Macromolecule #2: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 2 / Number of copies: 10 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #3: HEXANE

MacromoleculeName: HEXANE / type: ligand / ID: 3 / Number of copies: 15 / Formula: HEX
Molecular weightTheoretical: 86.175 Da
Chemical component information

ChemComp-HEX:
HEXANE

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Macromolecule #4: DODECANE

MacromoleculeName: DODECANE / type: ligand / ID: 4 / Number of copies: 10 / Formula: D12
Molecular weightTheoretical: 170.335 Da
Chemical component information

ChemComp-D12:
DODECANE

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Macromolecule #5: DECANE

MacromoleculeName: DECANE / type: ligand / ID: 5 / Number of copies: 10 / Formula: D10
Molecular weightTheoretical: 142.282 Da
Chemical component information

ChemComp-D10:
DECANE

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Macromolecule #6: (1aR,2aR,3S,6R,6aS,8aS,8bR,9R)-2a-hydroxy-8b-methyl-9-(prop-1-en-...

MacromoleculeName: (1aR,2aR,3S,6R,6aS,8aS,8bR,9R)-2a-hydroxy-8b-methyl-9-(prop-1-en-2-yl)hexahydro-3,6-methano-1,5,7-trioxacyclopenta[ij]c yclopropa[a]azulene-4,8(3H)-dione
type: ligand / ID: 6 / Number of copies: 1 / Formula: RI5
Molecular weightTheoretical: 292.284 Da

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Macromolecule #7: water

MacromoleculeName: water / type: ligand / ID: 7 / Number of copies: 132 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 298 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 41.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.8000000000000003 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 214978
Initial angle assignmentType: PROJECTION MATCHING
Final angle assignmentType: PROJECTION MATCHING

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