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Yorodumi- EMDB-29520: Structure of the amino-terminal domain of kainate receptor GluK2 ... -
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-Basic information
Entry | Database: EMDB / ID: EMD-29520 | |||||||||
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Title | Structure of the amino-terminal domain of kainate receptor GluK2 in complex with the positive allosteric modulator BPAM344 and noncompetitive inhibitor perampanel | |||||||||
Map data | Structure of the amino-terminal domain of kainate receptor GluK2 in complex with the positive allosteric modulator BPAM344 and noncompetitive inhibitor perampanel | |||||||||
Sample |
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Keywords | iGluR / Kainate receptor / positive allosteric modulator / Perampanel / 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 / 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 / extracellularly glutamate-gated ion channel activity / regulation of JNK cascade / kainate selective glutamate receptor activity / ionotropic glutamate receptor complex / behavioral fear response / neuronal action potential / 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 / synaptic transmission, glutamatergic / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / 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 / perikaryon / postsynaptic membrane / neuron apoptotic process / negative regulation of neuron apoptotic process / postsynaptic density / axon / neuronal cell body / glutamatergic synapse / dendrite / ubiquitin protein ligase binding / synapse / identical protein binding / membrane / plasma membrane Similarity search - Function | |||||||||
Biological species | Rattus norvegicus (Norway rat) | |||||||||
Method | single particle reconstruction / cryo EM / Resolution: 3.03 Å | |||||||||
Authors | Gangwar SP / Yen LY / Yelshanskaya MV / Sobolevsky AI | |||||||||
Funding support | United States, 2 items
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Citation | Journal: Cell Rep / Year: 2023 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 | emd_29520.map.gz | 259.2 MB | EMDB map data format | |
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Header (meta data) | emd-29520-v30.xml emd-29520.xml | 16.3 KB 16.3 KB | Display Display | EMDB header |
FSC (resolution estimation) | emd_29520_fsc.xml | 13.7 KB | Display | FSC data file |
Images | emd_29520.png | 59.6 KB | ||
Filedesc metadata | emd-29520.cif.gz | 6.3 KB | ||
Others | emd_29520_half_map_1.map.gz emd_29520_half_map_2.map.gz | 254.4 MB 254.4 MB | ||
Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-29520 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-29520 | HTTPS FTP |
-Validation report
Summary document | emd_29520_validation.pdf.gz | 937.6 KB | Display | EMDB validaton report |
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Full document | emd_29520_full_validation.pdf.gz | 937.2 KB | Display | |
Data in XML | emd_29520_validation.xml.gz | 22.8 KB | Display | |
Data in CIF | emd_29520_validation.cif.gz | 29.7 KB | Display | |
Arichive directory | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-29520 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-29520 | HTTPS FTP |
-Related structure data
Related structure data | 8fwvMC 8fwqC 8fwrC 8fwsC 8fwtC 8fwuC 8fwwC M: atomic model generated by this map C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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Related items in Molecule of the Month |
-Map
File | Download / File: emd_29520.map.gz / Format: CCP4 / Size: 274.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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Annotation | Structure of the amino-terminal domain of kainate receptor GluK2 in complex with the positive allosteric modulator BPAM344 and noncompetitive inhibitor perampanel | ||||||||||||||||||||||||||||||||||||
Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
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 amino-terminal domain of kainate receptor...
File | emd_29520_half_map_1.map | ||||||||||||
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Annotation | Structure of the amino-terminal domain 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 amino-terminal domain of kainate receptor...
File | emd_29520_half_map_2.map | ||||||||||||
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Annotation | Structure of the amino-terminal domain of kainate receptor GluK2 in complex with the positive allosteric modulator BPAM344 and noncompetitive inhibitor perampanel | ||||||||||||
Projections & Slices |
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Density Histograms |
-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 / Parent: 0 / Macromolecule list: #1 / Details: Map displaying amino-terminal domain |
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Source (natural) | Organism: Rattus norvegicus (Norway rat) |
-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: Rattus norvegicus (Norway rat) |
Molecular weight | Theoretical: 102.509977 KDa |
Recombinant expression | Organism: Homo sapiens (human) |
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 UniProtKB: Glutamate receptor ionotropic, kainate 2 |
-Macromolecule #4: 2-acetamido-2-deoxy-beta-D-glucopyranose
Macromolecule | Name: 2-acetamido-2-deoxy-beta-D-glucopyranose / type: ligand / ID: 4 / Number of copies: 8 / Formula: NAG |
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Molecular weight | Theoretical: 221.208 Da |
Chemical component information | ChemComp-NAG: |
-Experimental details
-Structure determination
Method | cryo EM |
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Processing | single particle reconstruction |
Aggregation state | particle |
-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 |
-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: FIELD EMISSION GUN |
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 |