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- EMDB-70667: Human delta 2 receptor with R710W Cerebellar Ataxia mutation in t... -

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Basic information

Entry
Database: EMDB / ID: EMD-70667
TitleHuman delta 2 receptor with R710W Cerebellar Ataxia mutation in the apo closed state
Map dataSharpened map
Sample
  • Complex: Human Delta-2 Receptor with the R710W cerebellar ataxia mutation
    • Protein or peptide: Glutamate receptor ionotropic, delta-2
KeywordsLigand-gated ion channel / ion channel / neurotransmitter receptor / TRANSPORT PROTEIN
Function / homology
Function and homology information


trans-synaptic protein complex / cerebellar granule cell differentiation / positive regulation of long-term synaptic depression / excitatory synapse assembly / synaptic signaling via neuropeptide / regulation of postsynaptic density assembly / glutamate receptor activity / positive regulation of synapse assembly / heterophilic cell-cell adhesion / glutamate receptor signaling pathway ...trans-synaptic protein complex / cerebellar granule cell differentiation / positive regulation of long-term synaptic depression / excitatory synapse assembly / synaptic signaling via neuropeptide / regulation of postsynaptic density assembly / glutamate receptor activity / positive regulation of synapse assembly / heterophilic cell-cell adhesion / glutamate receptor signaling pathway / parallel fiber to Purkinje cell synapse / regulation of neuron projection development / AMPA glutamate receptor activity / regulation of neuron apoptotic process / AMPA glutamate receptor complex / ionotropic glutamate receptor complex / regulation of presynapse assembly / prepulse inhibition / regulation of postsynaptic membrane neurotransmitter receptor levels / excitatory postsynaptic potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / PDZ domain binding / postsynaptic density membrane / modulation of chemical synaptic transmission / intracellular protein localization / scaffold protein binding / dendritic spine / synapse / glutamatergic synapse / metal ion binding / identical protein binding / plasma membrane
Similarity search - Function
Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I
Similarity search - Domain/homology
Glutamate receptor ionotropic, delta-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.68 Å
AuthorsWang H / Ahmed F / Khau J / Mondal AK / Twomey EC
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM154904 United States
CitationJournal: Nature / Year: 2025
Title: Delta-type glutamate receptors are ligand-gated ion channels.
Authors: Haobo Wang / Fairine Ahmed / Jeffrey Khau / Anish Kumar Mondal / Edward C Twomey /
Abstract: Delta-type ionotropic glutamate receptors (iGluRs), or GluDs, are members of the iGluR ligand-gated ion channel family, yet their function remains enigmatic. Although GluDs are widely expressed in ...Delta-type ionotropic glutamate receptors (iGluRs), or GluDs, are members of the iGluR ligand-gated ion channel family, yet their function remains enigmatic. Although GluDs are widely expressed in the brain, play key roles in synaptic organization, and harbor disease-linked mutations, whether they retain iGluR-like channel function is debated as currents have not been directly observed. Here, we define GluDs as ligand-gated ion channels that are tightly regulated in cellular contexts by purifying human GluD2 (hGluD2) and directly characterizing its structure and function using cryo-electron microscopy (cryoEM) and bilayer recordings. We show that hGluD2 is activated by D-serine and γ-aminobutyric acid (GABA), with augmented activation at physiological temperatures. We reveal that hGluD2 contains an ion channel directly coupled to clamshell-like ligand-binding domains (LBDs), which are coordinated by the amino terminal domain (ATD) above the ion channel. Ligand binding triggers channel opening via an asymmetric mechanism, and a cerebellar ataxia point mutation in the LBD rearranges the receptor architecture and induces leak currents. Our findings demonstrate that GluDs possess the intrinsic biophysical properties of ligand-gated ion channels, reconciling prior conflicting observations to establish a framework for understanding their cellular regulation and for developing therapies targeting GluD2.
History
DepositionMay 16, 2025-
Header (metadata) releaseSep 24, 2025-
Map releaseSep 24, 2025-
UpdateOct 1, 2025-
Current statusOct 1, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70667.png

Downloads & links

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Map

FileDownload / File: emd_70667.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.59 Å/pix.
x 256 pix.
= 407.04 Å		1.59 Å/pix.
x 256 pix.
= 407.04 Å		1.59 Å/pix.
x 256 pix.
= 407.04 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.59 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.25
Minimum - Maximum-1.5809803 - 2.4493585
Average (Standard dev.)-0.0010339455 (±0.034240607)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 407.04 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: unsharpened map

Fileemd_70667_additional_1.map
Annotationunsharpened map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Half map: half map a

Fileemd_70667_half_map_1.map
Annotationhalf map a
Projections & Slices
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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: half map b

Fileemd_70667_half_map_2.map
Annotationhalf map b
Projections & Slices
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Sample components

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Entire : Human Delta-2 Receptor with the R710W cerebellar ataxia mutation

EntireName: Human Delta-2 Receptor with the R710W cerebellar ataxia mutation
Components
  • Complex: Human Delta-2 Receptor with the R710W cerebellar ataxia mutation
    • Protein or peptide: Glutamate receptor ionotropic, delta-2

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Supramolecule #1: Human Delta-2 Receptor with the R710W cerebellar ataxia mutation

SupramoleculeName: Human Delta-2 Receptor with the R710W cerebellar ataxia mutation
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Glutamate receptor ionotropic, delta-2

MacromoleculeName: Glutamate receptor ionotropic, delta-2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 94.316406 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: IHIGAIFDES AKKDDEVFRT AVGDLNQNEE ILQTEKITFS VTFVDGNNPF QAVQEACELM NQGILALVSS IGCTSAGSLQ SLADAMHIP HLFIQRSTAG TPRSGCGLTR SNRNDDYTLS VRPPVYLHDV ILRVVTEYAW QKFIIFYDSE YDIRGIQEFL D KVSQQGMD ...String:
IHIGAIFDES AKKDDEVFRT AVGDLNQNEE ILQTEKITFS VTFVDGNNPF QAVQEACELM NQGILALVSS IGCTSAGSLQ SLADAMHIP HLFIQRSTAG TPRSGCGLTR SNRNDDYTLS VRPPVYLHDV ILRVVTEYAW QKFIIFYDSE YDIRGIQEFL D KVSQQGMD VALQKVENNI NKMITTLFDT MRIEELNRYR DTLRRAILVM NPATAKSFIT EVVETNLVAF DCHWIIINEE IN DVDVQEL VRRSIGRLTI IRQTFPVPQN ISQRCFRGNH RISSTLCDPK DPFAQNMEIS NLYIYDTVLL LANAFHKKLE DRK WHSMAS LSCIRKNSKP WQGGRSMLET IKKGGVSGLT GELEFGENGG NPNVHFEILG TNYGEELGRG VRKLGCWNPV TGLN GSLTD KKLENNMRGV VLRVVTVLEE PFVMVSENVL GKPKKYQGFS IDVLDALSNY LGFNYEIYVA PDHKYGSPQE DGTWN GLVG ELVFKRADIG ISALTITPDR ENVVDFTTRY MDYSVGVLLR RAEKTVDMFA CLAPFDLSLW ACIAGTVLLV GLLVYL LNW LNPPRLQMGS MTSTTLYNSM WFVYGSFVQQ GGEVPYTTLA TRMMMGAWWL FALIVISSYT ANLAAFLTIT RIESSIQ SL QDLSKQTEIP YGTVLDSAVY EHVRMKGLNP FERDSMYSQM WWMINRSNGS ENNVLESQAG IQKVKYGNYA FVWDAAVL E YVAINDPDCS FYTIGNTVAD RGYGIALQHG SPYRDVFSQR ILELQQNGDM DILKHKWWPK NGQCDLYSSV DTKQKGGAL DIKSFAGVFC ILAAGIVLSC FIAMLETWWN KRKGSR

UniProtKB: Glutamate receptor ionotropic, delta-2

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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

BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 45.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.9 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.68 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 153060
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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