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- PDB-6o9g: Open state GluA2 in complex with STZ and blocked by AgTx-636, aft... -

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Entry
Database: PDB / ID: 6o9g
TitleOpen state GluA2 in complex with STZ and blocked by AgTx-636, after micelle signal subtraction
ComponentsGlutamate receptor 2,Voltage-dependent calcium channel gamma-2 subunit
KeywordsTRANSPORT PROTEIN / Ion channel
Function / homologyReceptor, ligand binding region / Ionotropic glutamate receptor, metazoa / Ligand-gated ion channel / PMP-22/EMP/MP20/Claudin superfamily / PMP-22/EMP/MP20/Claudin family / Receptor family ligand binding region / Voltage-dependent calcium channel, gamma-2 subunit / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor / Presynaptic depolarization and calcium channel opening ...Receptor, ligand binding region / Ionotropic glutamate receptor, metazoa / Ligand-gated ion channel / PMP-22/EMP/MP20/Claudin superfamily / PMP-22/EMP/MP20/Claudin family / Receptor family ligand binding region / Voltage-dependent calcium channel, gamma-2 subunit / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor / Presynaptic depolarization and calcium channel opening / Voltage-dependent calcium channel, gamma subunit / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Trafficking of AMPA receptors / Phase 0 - rapid depolarisation / Phase 2 - plateau phase / LGI-ADAM interactions / Periplasmic binding protein-like I / eye blink reflex / positive regulation of protein localization to basolateral plasma membrane / neurotransmitter receptor transport, postsynaptic endosome to lysosome / cerebellar mossy fiber / channel regulator activity / neurotransmitter receptor internalization / positive regulation of AMPA receptor activity / regulation of AMPA receptor activity / postsynaptic neurotransmitter receptor diffusion trapping / membrane hyperpolarization / voltage-gated calcium channel complex / protein targeting to membrane / somatodendritic compartment / neuromuscular junction development / membrane depolarization / transmission of nerve impulse / postsynaptic density membrane / voltage-gated calcium channel activity / AMPA glutamate receptor activity / asymmetric synapse / ionotropic glutamate receptor binding / AMPA glutamate receptor complex / kainate selective glutamate receptor activity / ionotropic glutamate receptor complex / response to lithium ion / regulation of receptor recycling / immunoglobulin binding / positive regulation of synaptic transmission, glutamatergic / calcium channel activity / positive regulation of synaptic transmission / integral component of postsynaptic membrane / SNARE binding / regulation of synaptic transmission, glutamatergic / response to fungicide / integral component of postsynaptic density membrane / transmitter-gated ion channel activity involved in regulation of postsynaptic membrane potential / ionotropic glutamate receptor activity / ionotropic glutamate receptor signaling pathway / cytoskeletal protein binding / dendritic shaft / hippocampal mossy fiber to CA3 synapse / Schaffer collateral - CA1 synapse / synaptic vesicle membrane / receptor internalization / dendrite cytoplasm / PDZ domain binding / integral component of presynaptic membrane / endocytic vesicle membrane / terminal bouton / presynaptic membrane / response to calcium ion / establishment of protein localization / protein tetramerization / chemical synaptic transmission / growth cone / amyloid-beta binding / ATPase binding / perikaryon / signaling receptor activity / dendritic spine / postsynaptic density / cell junction / synapse / glutamatergic synapse / dendrite / endoplasmic reticulum membrane / neuronal cell body / protein kinase binding / integral component of plasma membrane / cell surface / protein-containing complex / identical protein binding / plasma membrane / cytosol / Glutamate receptor 2 / Voltage-dependent calcium channel gamma-2 subunit
Function and homology information
Specimen sourceRattus norvegicus (Norway rat)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.8 Å
AuthorsTwomey, E.C. / Yelshanskaya, M.V. / Vassilevski, A.A. / Sobolevsky, A.I.
Funding supportUnited States , 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and StrokeNS093838United States
National Institutes of Health/National Institute of Neurological Disorders and StrokeNS083660United States
National Institutes of Health/National Cancer InstituteCA206573United States
CitationJournal: Neuron / Year: 2018
Title: Mechanisms of Channel Block in Calcium-Permeable AMPA Receptors.
Authors: Edward C Twomey / Maria V Yelshanskaya / Alexander A Vassilevski / Alexander I Sobolevsky /
Abstract: AMPA receptors mediate fast excitatory neurotransmission and are critical for CNS development and function. Calcium-permeable subsets of AMPA receptors are strongly implicated in acute and chronic ...AMPA receptors mediate fast excitatory neurotransmission and are critical for CNS development and function. Calcium-permeable subsets of AMPA receptors are strongly implicated in acute and chronic neurological disorders. However, despite the clinical importance, the therapeutic landscape for specifically targeting them, and not the calcium-impermeable AMPA receptors, remains largely undeveloped. To address this problem, we used cryo-electron microscopy and electrophysiology to investigate the mechanisms by which small-molecule blockers selectively inhibit ion channel conductance in calcium-permeable AMPA receptors. We determined the structures of calcium-permeable GluA2 AMPA receptor complexes with the auxiliary subunit stargazin bound to channel blockers, including the orb weaver spider toxin AgTx-636, the spider toxin analog NASPM, and the adamantane derivative IEM-1460. Our structures provide insights into the architecture of the blocker binding site and the mechanism of trapping, which are critical for development of small molecules that specifically target calcium-permeable AMPA receptors.
Validation Report
SummaryFull reportAbout validation report
DateDeposition: Mar 13, 2019 / Release: Mar 20, 2019

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Assembly

Deposited unit
A: Glutamate receptor 2,Voltage-dependent calcium channel gamma-2 subunit
B: Glutamate receptor 2,Voltage-dependent calcium channel gamma-2 subunit
C: Glutamate receptor 2,Voltage-dependent calcium channel gamma-2 subunit
D: Glutamate receptor 2,Voltage-dependent calcium channel gamma-2 subunit
hetero molecules


Theoretical massNumber of molelcules
Total (without water)463,49913
Polyers460,7144
Non-polymers2,7859
Water0
1


TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein/peptide
Glutamate receptor 2,Voltage-dependent calcium channel gamma-2 subunit / GluR-2 / AMPA-selective glutamate receptor 2 / GluR-B / GluR-K2 / Glutamate receptor ionotropic / AMPA 2 / GluA2 / Neuronal voltage-gated calcium channel gamma-2 subunit / Transmembrane AMPAR regulatory protein gamma-2 / TARP gamma-2


Mass: 115178.531 Da / Num. of mol.: 4
Source: (gene. exp.) Rattus norvegicus (Norway rat), (gene. exp.) Homo sapiens (human)
Gene: Gria2, Glur2, CACNG2 / Production host: Homo sapiens (human) / References: UniProt: P19491, UniProt: Q9Y698
#2: Chemical
ChemComp-GLU / GLUTAMIC ACID


Mass: 147.129 Da / Num. of mol.: 4 / Formula: C5H9NO4 / Glutamic acid
#3: Chemical
ChemComp-CYZ / CYCLOTHIAZIDE / 3-BICYCLO[2.2.1]HEPT-5-EN-2-YL-6-CHLORO-3,4- DIHYDRO-2H-1,2,4-BENZOTHIADIAZINE-7-SULFONAMIDE 1,1 DIOXIDE


Mass: 389.878 Da / Num. of mol.: 4 / Formula: C14H16ClN3O4S2 / Cyclothiazide
#4: Chemical ChemComp-LU7 / N~1~-{5-[(3-{[3-(L-arginylamino)propyl]amino}propyl)amino]pentyl}-N~2~-[(2,4-dihydroxyphenyl)acetyl]-L-aspartamide / Argiotoxin 636


Mass: 636.787 Da / Num. of mol.: 1 / Formula: C29H52N10O6

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: GLuA2-STZ complex in activated state blocked by AgTx-636
Type: COMPLEX / Entity ID: 1 / Source: MULTIPLE SOURCES
Source (natural)Organism: Rattus norvegicus (Norway rat)
Source (recombinant)Cell: HEK293 gnti- / Organism: Homo sapiens (human)
Buffer solutionpH: 8
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy
Image recordingElectron dose: 55 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING ONLY
3D reconstructionResolution: 4.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 31129 / Symmetry type: POINT

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