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- EMDB-27553: Cryo-EM structure of human Glycine Receptor alpha1-beta heteromer... -

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Basic information

Entry
Database: EMDB / ID: EMD-27553
TitleCryo-EM structure of human Glycine Receptor alpha1-beta heteromer, apo state
Map data
Sample
  • Complex: heteromeric glycine receptor alpha-1 and beta, apo state
    • Protein or peptide: Glycine receptor subunit alpha-1
    • Protein or peptide: Glycine receptor subunit beta,Green fluorescent protein,Glycine receptor beta
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: HEXANE
  • Ligand: UNDECANE
  • Ligand: nonane
  • Ligand: N-BUTANE
  • Ligand: HEPTANE
  • Ligand: DECANE
  • Ligand: CHLORIDE IONChloride
Keywordsglycine receptor subunit alpha-1 / glycine receptor subunit beta / Green fluorescent protein / MEMBRANE 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 / acrosome reaction / positive regulation of acrosome reaction / gamma-aminobutyric acid receptor clustering / 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 / acrosome reaction / positive regulation of acrosome reaction / gamma-aminobutyric acid receptor clustering / 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 / regulation of membrane potential / visual perception / 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 / dendrite / synapse / 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
Glycine receptor beta / Glycine receptor subunit alpha-1 / Green fluorescent protein / Glycine receptor subunit beta
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.55 Å
AuthorsLiu X / Wang W
Funding support United States, 1 items
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, 2022-
Header (metadata) releaseOct 11, 2023-
Map releaseOct 11, 2023-
UpdateNov 1, 2023-
Current statusNov 1, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_27553.png

Downloads & links

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Map

FileDownload / File: emd_27553.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.83 Å
Density
Contour LevelBy AUTHOR: 0.28
Minimum - Maximum-1.7627602 - 2.3892946
Average (Standard dev.)0.008377861 (±0.08616942)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 239.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_27553_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_27553_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : heteromeric glycine receptor alpha-1 and beta, apo state

EntireName: heteromeric glycine receptor alpha-1 and beta, apo state
Components
  • Complex: heteromeric glycine receptor alpha-1 and beta, apo state
    • Protein or peptide: Glycine receptor subunit alpha-1
    • Protein or peptide: Glycine receptor subunit beta,Green fluorescent protein,Glycine receptor beta
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: HEXANE
  • Ligand: UNDECANE
  • Ligand: nonane
  • Ligand: N-BUTANE
  • Ligand: HEPTANE
  • Ligand: DECANE
  • Ligand: CHLORIDE IONChloride

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Supramolecule #1: heteromeric glycine receptor alpha-1 and beta, apo state

SupramoleculeName: heteromeric glycine receptor alpha-1 and beta, apo state
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 240 KDa

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Macromolecule #1: Glycine receptor subunit alpha-1

MacromoleculeName: Glycine receptor subunit alpha-1 / type: protein_or_peptide / ID: 1
Details: Derived by substitution of M3/M4 loop (residues R316-P381) s by GSSG peptide.
Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.421113 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: ARSAPKPMSP SDFLDKLMGR TSGYDARIRP NFKGPPVNVS CNIFINSFGS IAETTMDYRV NIFLRQQWND PRLAYNEYPD DSLDLDPSM LDSIWKPDLF FANEKGAHFH EITTDNKLLR ISRNGNVLYS IRITLTLACP MDLKNFPMDV QTCIMQLESF G YTMNDLIF ...String:
ARSAPKPMSP SDFLDKLMGR TSGYDARIRP NFKGPPVNVS CNIFINSFGS IAETTMDYRV NIFLRQQWND PRLAYNEYPD DSLDLDPSM LDSIWKPDLF FANEKGAHFH EITTDNKLLR ISRNGNVLYS IRITLTLACP MDLKNFPMDV QTCIMQLESF G YTMNDLIF EWQEQGAVQV ADGLTLPQFI LKEEKDLRYC TKHYNTGKFT CIEARFHLER QMGYYLIQMY IPSLLIVILS WI SFWINMD AAPARVGLGI TTVLTMTTQS SGSRASLPKV SYVKAIDIWM AVCLLFVFSA LLEYAAVNFV SRQHKELLGS SGE EMRKLF IQRAKKIDKI SRIGFPMAFL IFNMFYWIIY KIVRREDVHN Q

UniProtKB: Glycine receptor subunit alpha-1

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Macromolecule #2: Glycine receptor subunit beta,Green fluorescent protein,Glycine r...

MacromoleculeName: Glycine receptor subunit beta,Green fluorescent protein,Glycine receptor beta
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 76.584531 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: KSSKKGKGKK KQYLCPSQQS AEDLARVPAN STSNILNRLL VSYDPRIRPN FKGIPVDVVV NIFINSFGSI QETTMDYRVN IFLRQKWND PRLKLPSDFR GSDALTVDPT MYKCLWKPDL FFANEKSANF HDVTQENILL FIFRDGDVLV SMRLSITLSC P LDLTLFPM ...String:
KSSKKGKGKK KQYLCPSQQS AEDLARVPAN STSNILNRLL VSYDPRIRPN FKGIPVDVVV NIFINSFGSI QETTMDYRVN IFLRQKWND PRLKLPSDFR GSDALTVDPT MYKCLWKPDL FFANEKSANF HDVTQENILL FIFRDGDVLV SMRLSITLSC P LDLTLFPM DTQRCKMQLE SFGYTTDDLR FIWQSGDPVQ LEKIALPQFD IKKEDIEYGN CTKYYKGTGY YTCVEVIFTL RR QVGFYMM GVYAPTLLIV VLSWLSFWIN PDASAARVPL GIFSVLSLAS ECTTLAAELP KVSYVKALDV WLIACLLFGF ASL VEYAVV QVMLNGGSSA AAVSKGEELF TGVVPILVEL DGDVNGHKFS VSGEGEGDAT YGKLTLKFIC TTGKLPVPWP TLVT TFSYG VQCFSRYPDH MKQHDFFKSA MPEGYVQERT IFFKDDGNYK TRAEVKFEGD TLVNRIELKG IDFKEDGNIL GHKLE YNYN SHNVYIMADK QKNGIKVNFK IRHNIEDGSV QLADHYQQNT PIGDGPVLLP DNHYLSTQSA LSKDPNEKRD HMVLLE FVT AAGITHGMDE LYKSGSGSGV GETRCKKVCT SKSDLRSNDF SIVGSLPRDF ELSNYDCYGK PIEVNNGLGK SQAKNNK KP PPAKPVIPTA AKRIDLYARA LFPFCFLFFN VIYWSIYL

UniProtKB: Glycine receptor subunit beta, Green fluorescent protein, Glycine receptor beta

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Macromolecule #3: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 3 / Number of copies: 5 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

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Macromolecule #4: HEXANE

MacromoleculeName: HEXANE / type: ligand / ID: 4 / Number of copies: 15 / Formula: HEX
Molecular weightTheoretical: 86.175 Da
Chemical component information

ChemComp-HEX:
HEXANE / Hexane

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Macromolecule #5: UNDECANE

MacromoleculeName: UNDECANE / type: ligand / ID: 5 / Number of copies: 12 / Formula: UND
Molecular weightTheoretical: 156.308 Da
Chemical component information

ChemComp-UND:
UNDECANE / Undecane

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Macromolecule #6: nonane

MacromoleculeName: nonane / type: ligand / ID: 6 / Number of copies: 13 / Formula: DD9
Molecular weightTheoretical: 128.255 Da
Chemical component information

ChemComp-DD9:
nonane / Nonane

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Macromolecule #7: N-BUTANE

MacromoleculeName: N-BUTANE / type: ligand / ID: 7 / Number of copies: 5 / Formula: NBU
Molecular weightTheoretical: 58.122 Da
Chemical component information

ChemComp-NBU:
N-BUTANE / Butane

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Macromolecule #8: HEPTANE

MacromoleculeName: HEPTANE / type: ligand / ID: 8 / Number of copies: 8 / Formula: HP6
Molecular weightTheoretical: 100.202 Da
Chemical component information

ChemComp-HP6:
HEPTANE / Heptane

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Macromolecule #9: DECANE

MacromoleculeName: DECANE / type: ligand / ID: 9 / Number of copies: 1 / Formula: D10
Molecular weightTheoretical: 142.282 Da
Chemical component information

ChemComp-D10:
DECANE / Decane

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Macromolecule #10: CHLORIDE ION

MacromoleculeName: CHLORIDE ION / type: ligand / ID: 10 / Number of copies: 2 / Formula: CL
Molecular weightTheoretical: 35.453 Da

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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

Concentration6 mg/mL
BufferpH: 8
Component:
ConcentrationFormulaName
200.0 mMNaClSodium chloridesodium chloride
20.0 mMTris-HClTrisTris-HClTris
0.06 % w/vdigitonindigitonin
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 400 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 70 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 %

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Sample stageSpecimen holder model: GATAN LIQUID NITROGEN / Cooling holder cryogen: NITROGEN
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 69.6 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7mly

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.55 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 29850

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Atomic model buiding 1

Initial modelPDB ID:

7mly


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL
Output model

PDB-8dn3:
Cryo-EM structure of human Glycine Receptor alpha1-beta heteromer, apo state

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