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- PDB-9frg: CryoEM structure of human rho1 GABAA receptor in complex with (S)... -

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Basic information

Entry
Database: PDB / ID: 9frg
TitleCryoEM structure of human rho1 GABAA receptor in complex with (S)-GABOB in the desensitized state
ComponentsGamma-aminobutyric acid receptor subunit rho-1
KeywordsTRANSLOCASE / Ion channel
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 / intracellular vesicle / chloride channel complex / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / chloride transmembrane transport / modulation of chemical synaptic transmission ...GABA receptor activation / GABA-A receptor activity / GABA-gated chloride ion channel activity / GABA-A receptor complex / gamma-aminobutyric acid signaling pathway / intracellular vesicle / chloride channel complex / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / chloride transmembrane transport / modulation of chemical synaptic transmission / GABA-ergic synapse / presynaptic membrane / chemical synaptic transmission / postsynaptic membrane / protein domain specific binding / protein-containing complex binding / glutamatergic synapse / 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
: / DECANE / HEXANE / N-OCTANE / Gamma-aminobutyric acid receptor subunit rho-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.41 Å
AuthorsFan, C. / Howard, R.J. / Lindahl, E.
Funding support Sweden, 1items
OrganizationGrant numberCountry
Swedish Research Council2019-02433 Sweden
CitationJournal: Nat Commun / Year: 2025
Title: Cryo-EM structures of ρ1 GABA receptors with antagonist and agonist drugs.
Authors: Chen Fan / John Cowgill / Rebecca J Howard / Erik Lindahl /
Abstract: The family of ρ-type GABA receptors includes potential therapeutic targets in several neurological conditions, and features distinctive pharmacology compared to other subtypes. Here we report four ...The family of ρ-type GABA receptors includes potential therapeutic targets in several neurological conditions, and features distinctive pharmacology compared to other subtypes. Here we report four cryo-EM structures with previously unresolved ligands, electrophysiology recordings, and molecular dynamics simulations to characterize binding and conformational impact of the drugs THIP (a non-opioid analgesic), CGP36742 (a phosphinic acid) and GABOB (an anticonvulsant) on a human ρ1 GABA receptor. A distinctive binding pose of THIP in ρ1 versus α4β3δ GABA receptors offers a rationale for its inverse effects on these subtypes. CGP36742 binding is similar to the canonical ρ-type inhibitor TPMPA, supporting a shared mechanism of action among phosphinic acids. Binding of GABOB is similar to GABA, but produces a mixture of partially-locked and desensitized states, likely underlying weaker agonist activity. Together, these results elucidate interactions of a ρ-type GABA receptor with therapeutic drugs, offering mechanistic insights and a basis for further pharmaceutical development.
History
DepositionJun 18, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 2, 2025Provider: repository / Type: Initial release
Revision 1.1Jul 9, 2025Group: Data collection / Category: em_software / Item: _em_software.name
Revision 1.2Aug 13, 2025Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Gamma-aminobutyric acid receptor subunit rho-1
E: Gamma-aminobutyric acid receptor subunit rho-1
B: Gamma-aminobutyric acid receptor subunit rho-1
C: Gamma-aminobutyric acid receptor subunit rho-1
D: Gamma-aminobutyric acid receptor subunit rho-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)285,34547
Polymers279,7515
Non-polymers5,59442
Water99155
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein / Sugars , 2 types, 15 molecules AEBCD

#1: Protein
Gamma-aminobutyric acid receptor subunit rho-1 / GABA(A) receptor subunit rho-1 / GABA(C) receptor


Mass: 55950.230 Da / Num. of mol.: 5
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GABRR1 / Production host: Homo sapiens (human) / References: UniProt: P24046
#2: Sugar
ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 6 types, 87 molecules

#3: Chemical
ChemComp-D10 / DECANE


Mass: 142.282 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C10H22
#4: Chemical
ChemComp-OCT / N-OCTANE


Mass: 114.229 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C8H18
#5: Chemical
ChemComp-HEX / HEXANE


Mass: 86.175 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C6H14
#6: Chemical
ChemComp-A1IFH / (S)-amino-3-hydroxybutanoic acid / (S)-GABOB


Mass: 119.119 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C4H9NO3 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 55 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human rho1 GABAA receptor / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 47 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.41 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 57366 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00714170
ELECTRON MICROSCOPYf_angle_d1.1619200
ELECTRON MICROSCOPYf_dihedral_angle_d13.5125000
ELECTRON MICROSCOPYf_chiral_restr0.0672190
ELECTRON MICROSCOPYf_plane_restr0.0152330

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