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- EMDB-48904: Composite map for GluK2-1xNeto2 in the open state, in complex wit... -

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Entry
Database: EMDB / ID: EMD-48904
TitleComposite map for GluK2-1xNeto2 in the open state, in complex with the positive allosteric modulator BPAM344 and agonist kainate
Map dataComposite map for GluK2-1xNeto2 in the open state, in complex with the positive allosteric modulator BPAM344 and agonist kainate
Sample
  • Complex: Composite map for GluK2-1xNeto2 in the open state, in complex with the positive allosteric modulator BPAM344 and agonist kainate
    • Protein or peptide: Glutamate receptor ionotropic, kainate 2
    • Protein or peptide: Neuropilin and tolloid-like protein 2
  • Ligand: 3-(CARBOXYMETHYL)-4-ISOPROPENYLPROLINE
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide
KeywordsKainate receptor / GluK2 / Ion Channel / Neto2 / MEMBRANE PROTEIN
Function / homology
Function and homology information


mossy fiber rosette / detection of cold stimulus involved in thermoception / Activation of Na-permeable kainate receptors / kainate selective glutamate receptor complex / Activation of Ca-permeable Kainate Receptor / regulation of short-term neuronal synaptic plasticity / glutamate receptor activity / negative regulation of synaptic transmission, glutamatergic / ubiquitin conjugating enzyme binding / regulation of JNK cascade ...mossy fiber rosette / detection of cold stimulus involved in thermoception / Activation of Na-permeable kainate receptors / kainate selective glutamate receptor complex / Activation of Ca-permeable Kainate Receptor / regulation of short-term neuronal synaptic plasticity / glutamate receptor activity / negative regulation of synaptic transmission, glutamatergic / ubiquitin conjugating enzyme binding / regulation of JNK cascade / inhibitory postsynaptic potential / neurotransmitter receptor localization to postsynaptic specialization membrane / receptor clustering / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / kainate selective glutamate receptor activity / modulation of excitatory postsynaptic potential / extracellularly glutamate-gated ion channel activity / ionotropic glutamate receptor complex / positive regulation of synaptic transmission / behavioral fear response / neuronal action potential / glutamate-gated receptor activity / glutamate-gated calcium ion channel activity / ionotropic glutamate receptor binding / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / presynaptic modulation of chemical synaptic transmission / dendrite cytoplasm / hippocampal mossy fiber to CA3 synapse / SNARE binding / regulation of membrane potential / excitatory postsynaptic potential / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / PDZ domain binding / regulation of long-term neuronal synaptic plasticity / postsynaptic density membrane / modulation of chemical synaptic transmission / terminal bouton / intracellular calcium ion homeostasis / positive regulation of neuron apoptotic process / presynaptic membrane / neuron apoptotic process / scaffold protein binding / perikaryon / chemical synaptic transmission / negative regulation of neuron apoptotic process / postsynaptic membrane / postsynaptic density / axon / neuronal cell body / ubiquitin protein ligase binding / dendrite / synapse / glutamatergic synapse / identical protein binding / membrane / plasma membrane
Similarity search - Function
CUB domain / Domain first found in C1r, C1s, uEGF, and bone morphogenetic protein. / CUB domain / CUB domain profile. / Spermadhesin, CUB domain superfamily / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A ...CUB domain / Domain first found in C1r, C1s, uEGF, and bone morphogenetic protein. / CUB domain / CUB domain profile. / Spermadhesin, CUB domain superfamily / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A, conserved site / LDL-receptor class A (LDLRA) domain signature. / LDL-receptor class A (LDLRA) domain profile. / Low-density lipoprotein receptor domain class A / Low-density lipoprotein (LDL) receptor class A repeat / LDL receptor-like superfamily / 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
Neuropilin and tolloid-like protein 2 / Glutamate receptor ionotropic, kainate 2
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.34 Å
AuthorsGangwar SP / Yelshanskaya MV / Yen LY / Newton TP / Sobolevsky AI
Funding support United States, 5 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01 NS083660 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01 NS107253 United States
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)R01 AR078814 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R01 CA206573 United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R21 NS139087 United States
CitationJournal: Nat Struct Mol Biol / Year: 2025
Title: Activation of kainate receptor GluK2-Neto2 complex.
Authors: Shanti Pal Gangwar / Maria V Yelshanskaya / Laura Y Yen / Thomas P Newton / Alexander I Sobolevsky /
Abstract: Kainate receptors (KARs) are tetrameric, ligand-gated ion channels of the ionotropic glutamate receptor family that mediate excitatory neurotransmission and modulate neuronal circuits and synaptic ...Kainate receptors (KARs) are tetrameric, ligand-gated ion channels of the ionotropic glutamate receptor family that mediate excitatory neurotransmission and modulate neuronal circuits and synaptic plasticity during development of the central nervous system. KARs are implicated in psychiatric and neurological diseases and represent a target of therapeutic intervention. Native KARs form complexes with neuropilin and tolloid-like auxiliary subunits (Neto1 and Neto2), which modulate their function, trafficking and synaptic localization. Here we present structures of rat GluK2 KAR in the apo closed state and in the open states activated by agonist kainate and positive allosteric modulator BPAM344, solved in the presence and absence of Neto2 using time-resolved cryo-electron microscopy. While the binding of Neto2 does not change the behavior of individual or dimeric ligand-binding domains (LBDs) or the ion channel, it prevents tightening of the interface between two LBD dimers during activation and slows the kinetics of deactivation. Our structures illuminate the mechanism of KAR activation and its modulation by Neto2.
History
DepositionFeb 3, 2025-
Header (metadata) releaseSep 17, 2025-
Map releaseSep 17, 2025-
UpdateSep 17, 2025-
Current statusSep 17, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_48904.png

Downloads & links

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Map

FileDownload / File: emd_48904.map.gz / Format: CCP4 / Size: 216 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationComposite map for GluK2-1xNeto2 in the open state, in complex with the positive allosteric modulator BPAM344 and agonist kainate
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.83 Å/pix.
x 384 pix.
= 316.8 Å		0.83 Å/pix.
x 384 pix.
= 316.8 Å		0.83 Å/pix.
x 384 pix.
= 316.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 4.5
Minimum - Maximum-38.920451999999997 - 66.025540000000007
Average (Standard dev.)-0.013956752 (±1.2621783)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions384384384
Spacing384384384
CellA=B=C: 316.8 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Composite map for GluK2-1xNeto2 in the open state, in complex wit...

EntireName: Composite map for GluK2-1xNeto2 in the open state, in complex with the positive allosteric modulator BPAM344 and agonist kainate
Components
  • Complex: Composite map for GluK2-1xNeto2 in the open state, in complex with the positive allosteric modulator BPAM344 and agonist kainate
    • Protein or peptide: Glutamate receptor ionotropic, kainate 2
    • Protein or peptide: Neuropilin and tolloid-like protein 2
  • Ligand: 3-(CARBOXYMETHYL)-4-ISOPROPENYLPROLINE
  • Ligand: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
  • Ligand: 2-acetamido-2-deoxy-beta-D-glucopyranose
  • Ligand: 4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide

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Supramolecule #1: Composite map for GluK2-1xNeto2 in the open state, in complex wit...

SupramoleculeName: Composite map for GluK2-1xNeto2 in the open state, in complex with the positive allosteric modulator BPAM344 and agonist kainate
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Rattus norvegicus (Norway rat)

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Macromolecule #1: Glutamate receptor ionotropic, kainate 2

MacromoleculeName: Glutamate receptor ionotropic, kainate 2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 102.509977 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKIISPVLSN LVFSRSIKVL LCLLWIGYSQ GTTHVLRFGG IFEYVESGPM GAEELAFRFA VNTINRNRTL LPNTTLTYDT QKINLYDSF EASKKACDQL SLGVAAIFGP SHSSSANAVQ SICNALGVPH IQTRWKHQVS DNKDSFYVSL YPDFSSLSRA I LDLVQFFK ...String:
MKIISPVLSN LVFSRSIKVL LCLLWIGYSQ GTTHVLRFGG IFEYVESGPM GAEELAFRFA VNTINRNRTL LPNTTLTYDT QKINLYDSF EASKKACDQL SLGVAAIFGP SHSSSANAVQ SICNALGVPH IQTRWKHQVS DNKDSFYVSL YPDFSSLSRA I LDLVQFFK WKTVTVVYDD STGLIRLQEL IKAPSRYNLR LKIRQLPADT KDAKPLLKEM KRGKEFHVIF DCSHEMAAGI LK QALAMGM MTEYYHYIFT TLDLFALDVE PYRYSGVNMT GFRILNTENT QVSSIIEKWS MERLQAPPKP DSGLLDGFMT TDA ALMYDA VHVVSVAVQQ FPQMTVSSLQ CNRHKPWRFG TRFMSLIKEA HWEGLTGRIT FNKTNGLRTD FDLDVISLKE EGLE KIGTW DPASGLNMTE SQKGKPANIT DSLSNRSLIV TTILEEPYVL FKKSDKPLYG NDRFEGYCID LLRELSTILG FTYEI RLVE DGKYGAQDDV NGQWNGMVRE LIDHKADLAV APLAITYVRE KVIDFSKPFM TLGISILYRK PNGTNPGVFS FLNPLS PDI WMYVLLACLG VSCVLFVIAR FSPYEWYNPH PCNPDSDVVE NNFTLLNSFW FGVGALMQQG SELMPKALST RIVGGIW WF FTLIIISSYT ANLAAFLTVE RMESPIDSAD DLAKQTKIEY GAVEDGATMT FFKKSKISTY DKMWAFMSSR RQSVLVKS N EEGIQRVLTS DYAFLMESTT IEFVTQRNCN LTQIGGLIDS KGYGVGTPMG SPYRDKITIA ILQLQEEGKL HMMKEKWWR GNGCPEEESK EASALGVQNI GGIFIVLAAG LVLSVFVAVG EFLYKSKKNA QLEKRSFCSA MVEELRMSLK CQRRLKHKPQ APVIVKTEE VINMHTFNDR RLPGKETMA

UniProtKB: Glutamate receptor ionotropic, kainate 2

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Macromolecule #2: Neuropilin and tolloid-like protein 2

MacromoleculeName: Neuropilin and tolloid-like protein 2 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 59.413652 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MALEQLCAVL KVLLITVLVV EGIAVAQKTQ DGQNIGIKHV PATQCGIWVR TSNGGHFASP NYPDSYPPNK ECIYILEAAP RQRIELTFD ERYYIEPSFE CRFDHLEVRD GPFGFSPLID RYCGMKSPAL IRSTGRFMWI KFSSDEELEG LGFRAKYSFI P DPDFTYLG ...String:
MALEQLCAVL KVLLITVLVV EGIAVAQKTQ DGQNIGIKHV PATQCGIWVR TSNGGHFASP NYPDSYPPNK ECIYILEAAP RQRIELTFD ERYYIEPSFE CRFDHLEVRD GPFGFSPLID RYCGMKSPAL IRSTGRFMWI KFSSDEELEG LGFRAKYSFI P DPDFTYLG GILNPIPDCQ FELSGADGIV RSSQVEQEEK TKPGQAVDCI WTIKATPKAK IYLRFLDYQM EHSNECKRNF VA VYDGSSA IENLKAKFCS TVANDVMLKT GVGVIRMWAD EGSRLSRFRM LFTSFVEPPC TSSTFFCHSN MCINNSLVCN GVQ NCAYPW DENHCKEKKK AGLFEQITKT HGTIIGVTSG IVLVLLIISI LVQVKQPRKK VMACKTAFNK TGFQEVFDPP HYEL FSLRE KEISADLADL SEELDNYQKL RRSSTASRCI HDHHCGSQAS SVKQSRTNLS SMELPFRNDF AQPQPMKTFN STFKK SSYT FKQTHDCPEQ ALEDRVMEEI PCEIYVRGRD DSAQASISID F

UniProtKB: Neuropilin and tolloid-like protein 2

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Macromolecule #6: 3-(CARBOXYMETHYL)-4-ISOPROPENYLPROLINE

MacromoleculeName: 3-(CARBOXYMETHYL)-4-ISOPROPENYLPROLINE / type: ligand / ID: 6 / Number of copies: 4 / Formula: KAI
Molecular weightTheoretical: 213.23 Da
Chemical component information

ChemComp-KAI:
3-(CARBOXYMETHYL)-4-ISOPROPENYLPROLINE

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Macromolecule #7: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...

MacromoleculeName: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate
type: ligand / ID: 7 / Number of copies: 17 / Formula: POV
Molecular weightTheoretical: 760.076 Da
Chemical component information

ChemComp-POV:
(2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / phospholipid*YM

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Macromolecule #8: 2-acetamido-2-deoxy-beta-D-glucopyranose

MacromoleculeName: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 8 / Number of copies: 19 / Formula: NAG
Molecular weightTheoretical: 221.208 Da
Chemical component information

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

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Macromolecule #9: 4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-...

MacromoleculeName: 4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide
type: ligand / ID: 9 / Number of copies: 4 / Formula: 2J9
Molecular weightTheoretical: 242.27 Da
Chemical component information

ChemComp-2J9:
4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide

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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: 7.5
Component:
ConcentrationName
20.0 mMHEPES
150.0 mMSodium Chloride
0.05 %Digitonin
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 58.8 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 103436
Initial angle assignmentType: OTHER
Final angle assignmentType: OTHER

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