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- PDB-7pc0: GABA-A receptor bound by a-Cobratoxin -

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Basic information

Entry
Database: PDB / ID: 7pc0
TitleGABA-A receptor bound by a-Cobratoxin
Components
  • (Gamma-aminobutyric acid receptor subunit alpha- ...) x 2
  • Alpha-cobratoxin
  • Gamma-aminobutyric acid receptor subunit beta-3
  • Megabody 25
KeywordsMEMBRANE PROTEIN / neurotransmission / toxin / GABA
Function / homology
Function and homology information


GABA receptor complex / inhibitory extracellular ligand-gated monoatomic ion channel activity / GABA receptor activation / GABA-gated chloride ion channel activity / cellular response to histamine / inhibitory synapse assembly / GABA-A receptor activity / GABA-A receptor complex / acetylcholine receptor inhibitor activity / neurotransmitter receptor activity ...GABA receptor complex / inhibitory extracellular ligand-gated monoatomic ion channel activity / GABA receptor activation / GABA-gated chloride ion channel activity / cellular response to histamine / inhibitory synapse assembly / GABA-A receptor activity / GABA-A receptor complex / acetylcholine receptor inhibitor activity / neurotransmitter receptor activity / ion channel regulator activity / synaptic transmission, GABAergic / gamma-aminobutyric acid signaling pathway / roof of mouth development / Signaling by ERBB4 / chloride channel complex / GABA-ergic synapse / regulation of postsynaptic membrane potential / chloride transmembrane transport / dendrite membrane / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / cytoplasmic vesicle membrane / toxin activity / postsynapse / postsynaptic membrane / neuron projection / synapse / signal transduction / extracellular region / identical protein binding / plasma membrane
Similarity search - Function
: / Gamma-aminobutyric-acid A receptor, alpha 1 subunit / Gamma-aminobutyric-acid A receptor, beta subunit / : / Gamma-aminobutyric-acid A receptor, alpha subunit / Snake three-finger toxin / Snake toxins signature. / Snake toxin, conserved site / Snake toxin-like superfamily / Gamma-aminobutyric acid A receptor/Glycine receptor alpha ...: / Gamma-aminobutyric-acid A receptor, alpha 1 subunit / Gamma-aminobutyric-acid A receptor, beta subunit / : / Gamma-aminobutyric-acid A receptor, alpha subunit / Snake three-finger toxin / Snake toxins signature. / Snake toxin, conserved site / Snake toxin-like superfamily / 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
HEXANE / HISTAMINE / Alpha-cobratoxin / Gamma-aminobutyric acid receptor subunit alpha-1 / Gamma-aminobutyric acid receptor subunit beta-3
Similarity search - Component
Biological speciesLama glama (llama)
Homo sapiens (human)
Naja kaouthia (monocled cobra)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3 Å
AuthorsKasaragod, V.B. / Miller, P.S.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Wellcome Trust United Kingdom
CitationJournal: Nature / Year: 2022
Title: Mechanisms of inhibition and activation of extrasynaptic αβ GABA receptors.
Authors: Vikram Babu Kasaragod / Martin Mortensen / Steven W Hardwick / Ayla A Wahid / Valentina Dorovykh / Dimitri Y Chirgadze / Trevor G Smart / Paul S Miller /
Abstract: Type A GABA (γ-aminobutyric acid) receptors represent a diverse population in the mammalian brain, forming pentamers from combinations of α-, β-, γ-, δ-, ε-, ρ-, θ- and π-subunits. αβ, ...Type A GABA (γ-aminobutyric acid) receptors represent a diverse population in the mammalian brain, forming pentamers from combinations of α-, β-, γ-, δ-, ε-, ρ-, θ- and π-subunits. αβ, α4βδ, α6βδ and α5βγ receptors favour extrasynaptic localization, and mediate an essential persistent (tonic) inhibitory conductance in many regions of the mammalian brain. Mutations of these receptors in humans are linked to epilepsy and insomnia. Altered extrasynaptic receptor function is implicated in insomnia, stroke and Angelman and Fragile X syndromes, and drugs targeting these receptors are used to treat postpartum depression. Tonic GABAergic responses are moderated to avoid excessive suppression of neuronal communication, and can exhibit high sensitivity to Zn blockade, in contrast to synapse-preferring α1βγ, α2βγ and α3βγ receptor responses. Here, to resolve these distinctive features, we determined structures of the predominantly extrasynaptic αβ GABA receptor class. An inhibited state bound by both the lethal paralysing agent α-cobratoxin and Zn was used in comparisons with GABA-Zn and GABA-bound structures. Zn nullifies the GABA response by non-competitively plugging the extracellular end of the pore to block chloride conductance. In the absence of Zn, the GABA signalling response initially follows the canonical route until it reaches the pore. In contrast to synaptic GABA receptors, expansion of the midway pore activation gate is limited and it remains closed, reflecting the intrinsic low efficacy that characterizes the extrasynaptic receptor. Overall, this study explains distinct traits adopted by αβ receptors that adapt them to a role in tonic signalling.
History
DepositionAug 3, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 9, 2022Provider: repository / Type: Initial release
Revision 2.0Feb 16, 2022Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations / Polymer sequence / Source and taxonomy / Structure summary
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / em_entity_assembly / entity / entity_name_com / entity_poly / entity_poly_seq / entity_src_gen / entity_src_nat / pdbx_branch_scheme / pdbx_entity_branch / pdbx_entity_branch_descriptor / pdbx_entity_branch_link / pdbx_entity_branch_list / pdbx_entity_nonpoly / pdbx_nonpoly_scheme / pdbx_poly_seq_scheme / pdbx_struct_conn_angle / pdbx_struct_sheet_hbond / pdbx_unobs_or_zero_occ_residues / pdbx_validate_close_contact / pdbx_validate_polymer_linkage / pdbx_validate_torsion / struct_asym / struct_conf / struct_conn / struct_mon_prot_cis / struct_ref / struct_ref_seq / struct_ref_seq_dif / struct_sheet_range
Item: _atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_seq_id ..._atom_site_anisotrop.pdbx_auth_seq_id / _atom_site_anisotrop.pdbx_label_seq_id / _em_entity_assembly.entity_id_list / _entity_name_com.entity_id / _entity_name_com.name / _pdbx_branch_scheme.entity_id / _pdbx_entity_branch.entity_id / _pdbx_entity_branch_descriptor.entity_id / _pdbx_entity_branch_link.entity_id / _pdbx_entity_branch_list.entity_id / _pdbx_entity_nonpoly.entity_id / _pdbx_nonpoly_scheme.entity_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_sheet_hbond.range_1_auth_seq_id / _pdbx_struct_sheet_hbond.range_1_label_seq_id / _pdbx_struct_sheet_hbond.range_2_auth_seq_id / _pdbx_struct_sheet_hbond.range_2_label_seq_id / _pdbx_validate_close_contact.auth_seq_id_2 / _pdbx_validate_torsion.auth_seq_id / _struct_asym.entity_id / _struct_conf.beg_auth_seq_id / _struct_conf.beg_label_seq_id / _struct_conf.end_auth_seq_id / _struct_conf.end_label_seq_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_seq_id / _struct_mon_prot_cis.label_seq_id / _struct_mon_prot_cis.pdbx_label_seq_id_2 / _struct_ref.db_code / _struct_ref.db_name / _struct_ref.entity_id / _struct_ref.pdbx_align_begin / _struct_ref.pdbx_db_accession / _struct_ref.pdbx_seq_one_letter_code / _struct_sheet_range.beg_auth_seq_id / _struct_sheet_range.beg_label_seq_id / _struct_sheet_range.end_auth_seq_id / _struct_sheet_range.end_label_seq_id
Revision 2.1Feb 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 2.2Mar 2, 2022Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

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Assembly

Deposited unit
F: Megabody 25
A: Gamma-aminobutyric acid receptor subunit alpha-1
B: Gamma-aminobutyric acid receptor subunit beta-3
C: Gamma-aminobutyric acid receptor subunit beta-3
E: Gamma-aminobutyric acid receptor subunit beta-3
D: Gamma-aminobutyric acid receptor subunit alpha-1
K: Alpha-cobratoxin
L: Alpha-cobratoxin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)320,53919
Polymers315,9108
Non-polymers4,62911
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area37340 Å2
ΔGint-208 kcal/mol
Surface area74540 Å2

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Components

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Gamma-aminobutyric acid receptor subunit alpha- ... , 2 types, 2 molecules AD

#2: Protein Gamma-aminobutyric acid receptor subunit alpha-1 / GABA(A) receptor subunit alpha-1


Mass: 41991.133 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GABRA1 / Production host: Homo sapiens (human) / References: UniProt: P14867
#4: Protein Gamma-aminobutyric acid receptor subunit alpha-1 / GABA(A) receptor subunit alpha-1


Mass: 47059.648 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GABRA1 / Production host: Homo sapiens (human) / References: UniProt: P14867

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Protein , 2 types, 5 molecules BCEKL

#3: Protein Gamma-aminobutyric acid receptor subunit beta-3 / GABA(A) receptor subunit beta-3


Mass: 51615.117 Da / Num. of mol.: 3
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GABRB3 / Production host: Homo sapiens (human) / References: UniProt: P28472
#5: Protein Alpha-cobratoxin / Alpha-CT / Alpha-CbT / Alpha-Cbtx / Alpha-Ctx / Alpha-elapitoxin-Nk2a / Alpha-EPTX-Nk2a / Long ...Alpha-CT / Alpha-CbT / Alpha-Cbtx / Alpha-Ctx / Alpha-elapitoxin-Nk2a / Alpha-EPTX-Nk2a / Long neurotoxin 1 / Siamensis 3


Mass: 7842.094 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Naja kaouthia (monocled cobra) / References: UniProt: P01391

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Antibody , 1 types, 1 molecules F

#1: Antibody Megabody 25


Mass: 56329.621 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli)

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Sugars , 5 types, 8 molecules

#6: Polysaccharide alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)-[alpha-D- ...alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1235.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3[DManpa1-6]DManpa1-6[DManpa1-3]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,7,6/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3-3/a4-b1_b4-c1_c3-d1_c6-e1_e3-f1_e6-g1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][b-D-Manp]{[(3+1)][b-D-Manp]{}[(6+1)][b-D-Manp]{}}}}}LINUCSPDB-CARE
#7: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE
#8: Polysaccharide alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D- ...alpha-D-mannopyranose-(1-3)-alpha-D-mannopyranose-(1-6)-[alpha-D-mannopyranose-(1-3)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 1072.964 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-3DManpa1-6[DManpa1-3]DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,6,5/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3-3-3/a4-b1_b4-c1_c3-d1_c6-e1_e3-f1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(3+1)][a-D-Manp]{}[(6+1)][a-D-Manp]{[(3+1)][b-D-Manp]{}}}}}LINUCSPDB-CARE
#9: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][a-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#10: 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.: 4
Source method: isolated from a genetically manipulated source
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 , 3 types, 3 molecules

#11: Chemical ChemComp-HSM / HISTAMINE / Histamine


Mass: 111.145 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C5H9N3 / Feature type: SUBJECT OF INVESTIGATION / Comment: neurotransmitter, hormone*YM
#12: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
#13: Chemical ChemComp-HEX / HEXANE / Hexane


Mass: 86.175 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C6H14

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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

Component
IDNameTypeEntity IDParent-IDSource
1GABA-A receptor pentamer bound by CobratoxinCOMPLEX#1-#50MULTIPLE SOURCES
3GABA-A receptor pentamerCOMPLEX#2-#41RECOMBINANT
4CobratoxinCOMPLEX#51NATURAL
2Megabody 25COMPLEX#11RECOMBINANT
Molecular weightValue: 0.24 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Lama glama (llama)9844
23Homo sapiens (human)9606
34Naja kaouthia (monocled cobra)8649
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Escherichia coli (E. coli)562
23Homo sapiens (human)9606
Buffer solutionpH: 7.4
SpecimenConc.: 0.25 mg/ml / Embedding 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: SPOT SCAN
Electron lensMode: DIFFRACTION / Nominal defocus max: 1800 nm / Nominal defocus min: 600 nm
Image recordingAverage exposure time: 2.19 sec. / Electron dose: 50.69 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 78662 / Symmetry type: POINT

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