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- EMDB-40749: Structure of AMPA receptor GluA2 complex with auxiliary subunits ... -
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Open data
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Basic information
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Title | Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to glutamate and channel blocker spermidine (desensitized state) | |||||||||||||||
![]() | Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to glutamate and channel blocker spermidine (desensitized state) | |||||||||||||||
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Function / homology | ![]() neurotransmitter receptor transport, postsynaptic endosome to lysosome / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | |||||||||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() | |||||||||||||||
Method | ![]() ![]() | |||||||||||||||
![]() | Gangwar SP / Yen LY / Yelshanskaya MV / Sobolevsky AI | |||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Modulation of GluA2-γ5 synaptic complex desensitization, polyamine block and antiepileptic perampanel inhibition by auxiliary subunit cornichon-2. Authors: Shanti Pal Gangwar / Laura Y Yen / Maria V Yelshanskaya / Aryeh Korman / Drew R Jones / Alexander I Sobolevsky / ![]() Abstract: Synaptic complexes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission and can be targeted to treat ...Synaptic complexes of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs) with auxiliary subunits mediate most excitatory neurotransmission and can be targeted to treat neuropsychiatric and neurological disorders, including epilepsy. Here we present cryogenic-electron microscopy structures of rat GluA2 AMPAR complexes with inhibitory mouse γ5 and potentiating human cornichon-2 (CNIH2) auxiliary subunits. CNIH2 appears to destabilize the desensitized state of the complex by reducing the separation of the upper lobes in ligand-binding domain dimers. At the same time, CNIH2 stabilizes binding of polyamine spermidine to the selectivity filter of the closed ion channel. Nevertheless, CNIH2, and to a lesser extent γ5, attenuate polyamine block of the open channel and reduce the potency of the antiepileptic drug perampanel that inhibits the synaptic complex allosterically by binding to sites in the ion channel extracellular collar. These findings illustrate the fine-tuning of synaptic complex structure and function in an auxiliary subunit-dependent manner, which is critical for the study of brain region-specific neurotransmission and design of therapeutics for disease treatment. | |||||||||||||||
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) | ![]() ![]() | 20.7 KB 20.7 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 13.8 KB | Display | ![]() |
Images | ![]() | 75.4 KB | ||
Filedesc metadata | ![]() | 7 KB | ||
Others | ![]() ![]() | 254.9 MB 254.9 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8ssaMC ![]() 8bhfC ![]() 8ss2C ![]() 8ss3C ![]() 8ss4C ![]() 8ss5C ![]() 8ss6C ![]() 8ss7C ![]() 8ss8C ![]() 8ss9C ![]() 8ssbC 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 AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to glutamate and channel blocker spermidine (desensitized state) | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.83 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: #1
File | emd_40749_half_map_1.map | ||||||||||||
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Projections & Slices |
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Density Histograms |
-Half map: #2
File | emd_40749_half_map_2.map | ||||||||||||
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Density Histograms |
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Sample components
-Entire : GluA2-TARP gamma5-cornichon-2
Entire | Name: GluA2-TARP gamma5-cornichon-2 |
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Components |
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-Supramolecule #1: GluA2-TARP gamma5-cornichon-2
Supramolecule | Name: GluA2-TARP gamma5-cornichon-2 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2 Details: Structure of AMPA receptor GluA2 complex with auxiliary subunits TARP gamma-5 and cornichon-2 bound to competitive antagonist ZK and channel blocker spermidine (closed state) |
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Source (natural) | Organism: ![]() ![]() ![]() |
-Macromolecule #1: Glutamate receptor 2, Voltage-dependent calcium channel gamma-5 s...
Macromolecule | Name: Glutamate receptor 2, Voltage-dependent calcium channel gamma-5 subunit chimera type: protein_or_peptide / ID: 1 / Number of copies: 4 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() ![]() |
Molecular weight | Theoretical: 114.978859 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: NSIQIGGLFP RGADQEYSAF RVGMVQFSTS EFRLTPHIDN LEVANSFAVT NAFCSQFSRG VYAIFGFYDK KSVNTITSFC GTLHVSFIT PSFPTDGTHP FVIQMRPDLK GALLSLIEYY QWDKFAYLYD SDRGLSTLQA VLDSAAEKKW QVTAINVGNI N NDKKDETY ...String: NSIQIGGLFP RGADQEYSAF RVGMVQFSTS EFRLTPHIDN LEVANSFAVT NAFCSQFSRG VYAIFGFYDK KSVNTITSFC GTLHVSFIT PSFPTDGTHP FVIQMRPDLK GALLSLIEYY QWDKFAYLYD SDRGLSTLQA VLDSAAEKKW QVTAINVGNI N NDKKDETY RSLFQDLELK KERRVILDCE RDKVNDIVDQ VITIGKHVKG YHYIIANLGF TDGDLLKIQF GGAEVSGFQI VD YDDSLVS KFIERWSTLE EKEYPGAHTA TIKYTSALTY DAVQVMTEAF RNLRKQRIEI SRRGNAGDCL ANPAVPWGQG VEI ERALKQ VQVEGLSGNI KFDQNGKRIN YTINIMELKT NGPRKIGYWS EVDKMVLTED DTSGLEQKTV VVTTILESPY VMMK KNHEM LEGNERYEGY CVDLAAEIAK HCGFKYKLTI VGDGKYGARD ADTKIWNGMV GELVYGKADI AIAPLTITLV REEVI DFSK PFMSLGISIM IKKPQKSKPG VFSFLDPLAY EIWMCIVFAY IGVSVVLFLV SRFSPYEWHT EEFEDGRETQ SSESTN EFG IFNSLWFSLG AFMQQGCDIS PRSLSGRIVG GVWWFFTLII ISSYTANLAA FLTVERMVSP IESAEDLSKQ TEIAYGT LD SGSTKEFFRR SKIAVFDKMW TYMRSAEPSV FVRTTAEGVA RVRKSKGKYA YLLESTMNEY IEQRKPCDTM KVGGNLDS K GYGIATPKGS SLGTPVNLAV LKLSEQGVLD KLKNKWWYDK GECGAKDSGS KEKTSALSLS NVAGVFYILV GGLGLAMLV ALIEFCYKSR AEAKRMKGTG SACGRKALTL LSSVFAVCGL GLLGIAVSTD YWLYLEEGII LPQNQSTEVK MSLHSGLWRV CFLAGEERG RCFTIEYVMP MNSQMTSEST VNVLKMIRSA TPFPLVSLFF MFIGFILSNI GHIRPHRTIL AFVSGIFFIL S GLSLVVGL VLYISSINDE MLNRTKDAET YFNYKYGWSF AFAAISFLLT ESAGVMSVYL FMKRYTAE UniProtKB: ![]() |
-Macromolecule #2: Protein cornichon homolog 2
Macromolecule | Name: Protein cornichon homolog 2 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 18.94842 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MAFTFAAFCY MLTLVLCASL IFFVIWHIIA FDELRTDFKN PIDQGNPARA RERLKNIERI CCLLRKLVVP EYSIHGLFCL MFLCAAEWV TLGLNIPLLF YHLWRYFHRP ADGSEVMYDA VSIMNADILN YCQKESWCKL AFYLLSFFYY LYSMVYTLVS F UniProtKB: Protein cornichon homolog 2 |
-Macromolecule #3: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
Macromolecule | Name: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE / type: ligand / ID: 3 / Number of copies: 12 / Formula: PCW |
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Molecular weight | Theoretical: 787.121 Da |
Chemical component information | ![]() ChemComp-PCW: |
-Macromolecule #4: GLUTAMIC ACID
Macromolecule | Name: GLUTAMIC ACID / type: ligand / ID: 4 / Number of copies: 4 / Formula: GLU |
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Molecular weight | Theoretical: 147.129 Da |
Chemical component information | ![]() ChemComp-GLU: |
-Macromolecule #5: SPERMIDINE
Macromolecule | Name: SPERMIDINE / type: ligand / ID: 5 / Number of copies: 1 / Formula: SPD |
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Molecular weight | Theoretical: 145.246 Da |
Chemical component information | ![]() ChemComp-SPD: |
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Concentration | 4.5 mg/mL | |||||||||||||||
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Buffer | pH: 8 Component:
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Grid | Model: UltrAuFoil / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 25 sec. / Pretreatment - Atmosphere: AIR | |||||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV / Details: vitrification carried out in nitrogen atmosphere. | |||||||||||||||
Details | Protein extracted and purified in detergent micelle |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 100.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 58.0 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
Software | Name: ![]() |
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Output model | ![]() PDB-8ssa: |