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- PDB-8dn4: Cryo-EM structure of human Glycine Receptor alpha-1 beta heterome... -

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Basic information

Entry
Database: PDB / ID: 8dn4
TitleCryo-EM structure of human Glycine Receptor alpha-1 beta heteromer, glycine-bound state3(desensitized state)
Components(Glycine receptor subunit ...) x 2
KeywordsMEMBRANE PROTEIN / glycine receptor subunit alpha-1 / glycine receptor subunit beta / Green fluorescent protein
Function / homology
Function and homology information


taurine binding / response to alcohol / glycine-gated chloride channel complex / negative regulation of transmission of nerve impulse / Neurotransmitter receptors and postsynaptic signal transmission / positive regulation of acrosome reaction / gamma-aminobutyric acid receptor clustering / acrosome reaction / postsynaptic specialization / neuromuscular process controlling posture ...taurine binding / response to alcohol / glycine-gated chloride channel complex / negative regulation of transmission of nerve impulse / Neurotransmitter receptors and postsynaptic signal transmission / positive regulation of acrosome reaction / gamma-aminobutyric acid receptor clustering / acrosome reaction / postsynaptic specialization / neuromuscular process controlling posture / inhibitory synapse / extracellularly glycine-gated ion channel activity / righting reflex / regulation of respiratory gaseous exchange by nervous system process / extracellularly glycine-gated chloride channel activity / synaptic transmission, glycinergic / glycinergic synapse / inhibitory postsynaptic potential / cellular response to ethanol / adult walking behavior / chloride transport / cellular response to zinc ion / glycine binding / startle response / chloride channel complex / neuronal action potential / neuropeptide signaling pathway / GABA-ergic synapse / response to amino acid / monoatomic ion transport / chloride transmembrane transport / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / visual perception / regulation of membrane potential / bioluminescence / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / muscle contraction / generation of precursor metabolites and energy / cellular response to amino acid stimulus / transmembrane signaling receptor activity / nervous system development / perikaryon / chemical synaptic transmission / postsynaptic membrane / neuron projection / external side of plasma membrane / intracellular membrane-bounded organelle / neuronal cell body / synapse / dendrite / protein-containing complex binding / zinc ion binding / membrane / identical protein binding / plasma membrane / cytoplasm
Similarity search - Function
: / : / Glycine receptor beta / Glycine receptor alpha1 / Glycine receptor alpha / 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 ...: / : / Glycine receptor beta / Glycine receptor alpha1 / Glycine receptor alpha / 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 / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein
Similarity search - Domain/homology
nonane / HEXANE / PENTANE / N-BUTANE / N-OCTANE / Glycine receptor beta / Glycine receptor subunit alpha-1 / Green fluorescent protein / Glycine receptor subunit beta
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.1 Å
AuthorsLiu, X. / Wang, W.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)1R35GM146860 United States
CitationJournal: Nat Commun / Year: 2023
Title: Asymmetric gating of a human hetero-pentameric glycine receptor.
Authors: Xiaofen Liu / Weiwei Wang /
Abstract: Hetero-pentameric Cys-loop receptors constitute a major type of neurotransmitter receptors that enable signal transmission and processing in the nervous system. Despite intense investigations into ...Hetero-pentameric Cys-loop receptors constitute a major type of neurotransmitter receptors that enable signal transmission and processing in the nervous system. Despite intense investigations into their working mechanism and pharmaceutical potentials, how neurotransmitters activate these receptors remains unclear due to the lack of high-resolution structural information in the activated open state. Here we report near-atomic resolution structures resolved in digitonin consistent with all principle functional states of the human α1β GlyR, which is a major Cys-loop receptor that mediates inhibitory neurotransmission in the central nervous system of adults. Glycine binding induces cooperative and symmetric structural rearrangements in the neurotransmitter-binding extracellular domain but asymmetrical pore dilation in the transmembrane domain. Symmetric response in the extracellular domain is consistent with electrophysiological data showing cooperative glycine activation and contribution from both α1 and β subunits. A set of functionally essential but differentially charged amino acid residues in the transmembrane domain of the α1 and β subunits explains asymmetric activation. These findings provide a foundation for understanding how the gating of the Cys-loop receptor family members diverges to accommodate specific physiological environments.
History
DepositionJul 10, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 11, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 25, 2023Group: Database references / Category: citation
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
Revision 1.2Nov 1, 2023Group: Database references / Source and taxonomy / Structure summary
Category: entity / entity_name_com ...entity / entity_name_com / entity_src_gen / struct_ref / struct_ref_seq / struct_ref_seq_dif
Item: _entity.details / _entity.pdbx_description

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
D: Glycine receptor subunit alpha-1
A: Glycine receptor subunit alpha-1
B: Glycine receptor subunit alpha-1
C: Glycine receptor subunit alpha-1
E: Glycine receptor subunit beta,Green fluorescent protein,Glycine receptor beta
hetero molecules


Theoretical massNumber of molelcules
Total (without water)248,75425
Polymers246,3835
Non-polymers2,37120
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Glycine receptor subunit ... , 2 types, 5 molecules DABCE

#1: Protein
Glycine receptor subunit alpha-1 / / Glycine receptor 48 kDa subunit / Glycine receptor strychnine-binding subunit


Mass: 42421.113 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: Derived by substitution of M3/M4 loop (residues R316-P381) s by GSSG peptide.
Source: (gene. exp.) Homo sapiens (human) / Gene: GLRA1 / Production host: Homo sapiens (human) / References: UniProt: P23415
#2: Protein Glycine receptor subunit beta,Green fluorescent protein,Glycine receptor beta /


Mass: 76698.633 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GLRB, GFP / Production host: Homo sapiens (human)
References: UniProt: P48167, UniProt: P42212, UniProt: A0A2K6CAQ3

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Sugars , 1 types, 5 molecules

#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.: 5 / 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 , 5 types, 15 molecules

#4: Chemical ChemComp-LNK / PENTANE / Pentane


Mass: 72.149 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H12
#5: Chemical
ChemComp-HEX / HEXANE / Hexane


Mass: 86.175 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: C6H14
#6: Chemical ChemComp-NBU / N-BUTANE / Butane


Mass: 58.122 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C4H10
#7: Chemical ChemComp-OCT / N-OCTANE / Octane


Mass: 114.229 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H18
#8: Chemical ChemComp-DD9 / nonane / Nonane


Mass: 128.255 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H20

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Details

Has ligand of interestN

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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: heteromeric glycine receptor subunit alpha-1 and beta, glycine-bound state3(desensitized state)
Type: COMPLEX / Entity ID: #1-#2 / Source: RECOMBINANT
Molecular weightValue: 0.24 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 8
Buffer component
IDConc.NameFormulaBuffer-ID
1200 mMsodium chlorideNaClSodium chloride1
220 mMTris-HClTrisTris-HClTris1
30.06 % w/vdigitonindigitonin1
SpecimenConc.: 6 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationCryogen name: ETHANE / Humidity: 100 %

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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: 2500 nm / Nominal defocus min: 1000 nm / Alignment procedure: BASIC
Specimen holderCryogen: NITROGEN / Specimen holder model: GATAN LIQUID NITROGEN
Image recordingElectron dose: 69.6 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Version: 1.19.2_4158: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 4.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 30723 / Symmetry type: POINT
Atomic model buildingSpace: REAL
Atomic model buildingPDB-ID: 7MLY

7mly


Accession code: 7MLY / Source name: PDB / Type: experimental model

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