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- EMDB-70668: Human delta 2 receptor with R710W Cerebellar Ataxia mutation in t... -

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Basic information

Entry
Database: EMDB / ID: EMD-70668
TitleHuman delta 2 receptor with R710W Cerebellar Ataxia mutation in the apo leak state
Map datafull sharpened map
Sample
  • Complex: Human Delta-2 Receptor with the R710W cerebellar ataxia mutation
    • Protein or peptide: Human delta 2 receptor with R710W Cerebellar Ataxia mutation
KeywordsLigand-gated ion channel / ion channel / neurotransmitter receptor / TRANSPORT PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.73 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_70668.png

Downloads & links

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Map

FileDownload / File: emd_70668.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationfull sharpened map
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.59 Å/pix.
x 256 pix.
= 407.398 Å		1.59 Å/pix.
x 256 pix.
= 407.398 Å		1.59 Å/pix.
x 256 pix.
= 407.398 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.5914 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-1.7252307 - 2.269391
Average (Standard dev.)-0.0010471127 (±0.03400581)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 407.3984 Å
α=β=γ: 90.0 °

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Supplemental data

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Additional map: full unsharpened map

Fileemd_70668_additional_1.map
Annotationfull unsharpened map
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Additional map: LBD-TMD sharpened map

Fileemd_70668_additional_2.map
AnnotationLBD-TMD sharpened map
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Additional map: LBD-TMD half map a

Fileemd_70668_additional_3.map
AnnotationLBD-TMD half map a
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Additional map: LBD-TMD half map b

Fileemd_70668_additional_4.map
AnnotationLBD-TMD half map b
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Additional map: LBD-TMD unsharpened map

Fileemd_70668_additional_5.map
AnnotationLBD-TMD unsharpened map
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Half map: full map half a

Fileemd_70668_half_map_1.map
Annotationfull map half a
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Half map: full map half b

Fileemd_70668_half_map_2.map
Annotationfull map half b
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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: Human delta 2 receptor with R710W Cerebellar Ataxia mutation

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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: Human delta 2 receptor with R710W Cerebellar Ataxia mutation

MacromoleculeName: Human delta 2 receptor with R710W Cerebellar Ataxia mutation
type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 80.363031 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 TLATRMMMGA WWLFALIVIS SYTANLAAFL TITRIE SSI QSLQDLSKQT EIPYGTVLDS AVYEHVRMKG LNPFERDSMY SQMWWMINRS NGSENNVLES QAGIQKVKYG NYAFVWD AA VLEYVAINDP DCSFYTIGNT VADRGYGIAL QHGSPYRDVF SQRILELQQN GDMDILKHKW WPKNGQCD

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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: 3.73 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 131121
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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