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- PDB-8oq7: CryoEM structure of human rho1 GABAA receptor in complex with inh... -

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Basic information

Entry
Database: PDB / ID: 8oq7
TitleCryoEM structure of human rho1 GABAA receptor in complex with inhibitor TPMPA
ComponentsGamma-aminobutyric acid receptor subunit rho-1
KeywordsMEMBRANE PROTEIN / GABAA receptor / rho1
Function / homology
Function and homology information


GABA receptor activation / GABA-A receptor activity / GABA-A receptor complex / nervous system process / neurotransmitter receptor activity / gamma-aminobutyric acid signaling pathway / extracellular ligand-gated monoatomic ion channel activity / chloride channel activity / transmembrane transporter complex / chloride channel complex ...GABA receptor activation / GABA-A receptor activity / GABA-A receptor complex / nervous system process / neurotransmitter receptor activity / gamma-aminobutyric acid signaling pathway / extracellular ligand-gated monoatomic ion channel activity / chloride channel activity / transmembrane transporter complex / chloride channel 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 / signal transduction / 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 / DODECANE / HEXANE / N-OCTANE / Chem-VZA / Gamma-aminobutyric acid receptor subunit rho-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.2 Å
AuthorsChen, F. / Victor, T. / John, C. / Rebecca, J.H. / Lindahl, E.
Funding support Sweden, 1items
OrganizationGrant numberCountry
Swedish Research Council2019-02433 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, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 30, 2023Provider: repository / Type: Initial release
Revision 1.1Sep 13, 2023Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Nov 15, 2023Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.page_first
Revision 1.3Feb 7, 2024Group: Structure summary / Category: audit_author / Item: _audit_author.name

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


Theoretical massNumber of molelcules
Total (without water)287,83062
Polymers279,7515
Non-polymers8,07957
Water9,098505
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein / Sugars , 2 types, 15 molecules ABCDE

#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
#3: 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 / N-Acetylglucosamine


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 , 7 types, 552 molecules

#2: Chemical
ChemComp-VZA / methyl(1,2,3,6-tetrahydropyridin-4-yl)phosphinic acid / 1,2,5,6-Tetrahydropyridin-4-yl)methylphosphinic acid / TPMPA


Mass: 161.139 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C6H12NO2P / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-HEX / HEXANE / Hexane


Mass: 86.175 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: C6H14
#5: Chemical
ChemComp-OCT / N-OCTANE / Octane


Mass: 114.229 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C8H18
#6: Chemical
ChemComp-D12 / DODECANE / Dodecane


Mass: 170.335 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C12H26
#7: Chemical
ChemComp-D10 / DECANE / Decane


Mass: 142.282 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C10H22
#8: Chemical ChemComp-CL / CHLORIDE ION / Chloride


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


Mass: 18.015 Da / Num. of mol.: 505 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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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 / Humidity: 100 % / Chamber temperature: 298 K

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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 FIELDBright-field microscopy / Nominal defocus max: 2800 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 46.12 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM softwareName: EPU / Category: image acquisition
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 162880 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00614765
ELECTRON MICROSCOPYf_angle_d0.76319910
ELECTRON MICROSCOPYf_dihedral_angle_d11.0625445
ELECTRON MICROSCOPYf_chiral_restr0.0512225
ELECTRON MICROSCOPYf_plane_restr0.0052405

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