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- EMDB-29521: Structure of the ligand-binding and transmembrane domains of kain... -
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Open data
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Basic information
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Title | Structure of the ligand-binding and transmembrane domains of kainate receptor GluK2 in complex with the positive allosteric modulator BPAM344 and noncompetitive inhibitor perampanel | |||||||||
![]() | Structure of the ligand-binding and transmembrane domains of kainate receptor GluK2 in complex with the positive allosteric modulator BPAM344 and noncompetitive inhibitor perampanel | |||||||||
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Function / homology | ![]() 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 / negative regulation of synaptic transmission, glutamatergic / regulation of short-term neuronal synaptic plasticity / inhibitory postsynaptic potential / glutamate receptor activity / ubiquitin conjugating enzyme binding ...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 / negative regulation of synaptic transmission, glutamatergic / regulation of short-term neuronal synaptic plasticity / inhibitory postsynaptic potential / glutamate receptor activity / ubiquitin conjugating enzyme binding / receptor clustering / modulation of excitatory postsynaptic potential / regulation of JNK cascade / kainate selective glutamate receptor activity / ionotropic glutamate receptor complex / extracellularly glutamate-gated ion channel activity / neuronal action potential / behavioral fear response / positive regulation of synaptic transmission / glutamate-gated receptor activity / glutamate-gated calcium ion channel activity / 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 / regulation of membrane potential / SNARE binding / 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 / regulation of long-term neuronal synaptic plasticity / modulation of chemical synaptic transmission / terminal bouton / intracellular calcium ion homeostasis / positive regulation of neuron apoptotic process / presynaptic membrane / scaffold protein binding / chemical synaptic transmission / postsynaptic membrane / perikaryon / neuron apoptotic process / negative regulation of neuron apoptotic process / postsynaptic density / axon / neuronal cell body / glutamatergic synapse / ubiquitin protein ligase binding / synapse / dendrite / identical protein binding / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | ![]() ![]() | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.1 Å | |||||||||
![]() | Gangwar SP / Yen LY / Yelshanskaya MV / Sobolevsky AI | |||||||||
Funding support | ![]()
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![]() | ![]() Title: Positive and negative allosteric modulation of GluK2 kainate receptors by BPAM344 and antiepileptic perampanel. Authors: Shanti Pal Gangwar / Laura Y Yen / Maria V Yelshanskaya / Alexander I Sobolevsky / ![]() Abstract: Kainate receptors (KARs) are a subtype of ionotropic glutamate receptors that control synaptic transmission in the central nervous system and are implicated in neurological, psychiatric, and ...Kainate receptors (KARs) are a subtype of ionotropic glutamate receptors that control synaptic transmission in the central nervous system and are implicated in neurological, psychiatric, and neurodevelopmental disorders. Understanding the regulation of KAR function by small molecules is essential for exploring these receptors as drug targets. Here, we present cryoelectron microscopy (cryo-EM) structures of KAR GluK2 in complex with the positive allosteric modulator BPAM344, competitive antagonist DNQX, and negative allosteric modulator, antiepileptic drug perampanel. Our structures show that two BPAM344 molecules bind per ligand-binding domain dimer interface. In the absence of an agonist or in the presence of DNQX, BPAM344 stabilizes GluK2 in the closed state. The closed state is also stabilized by perampanel, which binds to the ion channel extracellular collar sites located in two out of four GluK2 subunits. The molecular mechanisms of positive and negative allosteric modulation of KAR provide a guide for developing new therapeutic strategies. | |||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 259.2 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 18.4 KB 18.4 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 13.7 KB | Display | ![]() |
Images | ![]() | 71 KB | ||
Others | ![]() ![]() | 254.4 MB 254.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8fwwMC ![]() 8fwqC ![]() 8fwrC ![]() 8fwsC ![]() 8fwtC ![]() 8fwuC ![]() 8fwvC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Structure of the ligand-binding and transmembrane domains of kainate receptor GluK2 in complex with the positive allosteric modulator BPAM344 and noncompetitive inhibitor perampanel | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.832 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Structure of the ligand-binding and transmembrane domains of...
File | emd_29521_half_map_1.map | ||||||||||||
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Annotation | Structure of the ligand-binding and transmembrane domains of kainate receptor GluK2 in complex with the positive allosteric modulator BPAM344 and noncompetitive inhibitor perampanel | ||||||||||||
Projections & Slices |
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Density Histograms |
-Half map: Structure of the ligand-binding and transmembrane domains of...
File | emd_29521_half_map_2.map | ||||||||||||
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Annotation | Structure of the ligand-binding and transmembrane domains of kainate receptor GluK2 in complex with the positive allosteric modulator BPAM344 and noncompetitive inhibitor perampanel | ||||||||||||
Projections & Slices |
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Density Histograms |
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Sample components
-Entire : GluK2
Entire | Name: GluK2 |
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Components |
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-Supramolecule #1: GluK2
Supramolecule | Name: GluK2 / type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1 Details: Map displaying ligand binding and transmembrane domain |
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Source (natural) | Organism: ![]() ![]() |
-Macromolecule #1: Glutamate receptor ionotropic, kainate 2
Macromolecule | Name: Glutamate receptor ionotropic, kainate 2 / type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 102.509977 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: 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 |
-Macromolecule #4: 4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-...
Macromolecule | Name: 4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide type: ligand / ID: 4 / Number of copies: 4 / Formula: 2J9 |
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Molecular weight | Theoretical: 242.27 Da |
Chemical component information | ![]() ChemComp-2J9: |
-Macromolecule #5: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(tri...
Macromolecule | Name: (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate type: ligand / ID: 5 / Number of copies: 16 / Formula: POV |
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Molecular weight | Theoretical: 760.076 Da |
Chemical component information | ![]() ChemComp-POV: |
-Macromolecule #6: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 6 / Number of copies: 2 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ![]() ChemComp-NAG: |
-Macromolecule #7: 2-(6'-oxo-1'-phenyl[1',6'-dihydro[2,3'-bipyridine]]-5'-yl)benzonitrile
Macromolecule | Name: 2-(6'-oxo-1'-phenyl[1',6'-dihydro[2,3'-bipyridine]]-5'-yl)benzonitrile type: ligand / ID: 7 / Number of copies: 2 / Formula: 6ZP |
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Molecular weight | Theoretical: 349.385 Da |
Chemical component information | ![]() ChemComp-6ZP: |
-Macromolecule #8: SODIUM ION
Macromolecule | Name: SODIUM ION / type: ligand / ID: 8 / Number of copies: 7 |
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Molecular weight | Theoretical: 22.99 Da |
-Macromolecule #9: CHLORIDE ION
Macromolecule | Name: CHLORIDE ION / type: ligand / ID: 9 / Number of copies: 2 / Formula: CL |
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Molecular weight | Theoretical: 35.453 Da |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 5 mg/mL | ||||||||||||
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Buffer | pH: 8 Component:
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Grid | Model: Quantifoil R1.2/1.3 / Pretreatment - Type: GLOW DISCHARGE | ||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 57.9 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: SPOT SCAN / 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 |