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- EMDB-15716: Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8... -
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Open data
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Basic information
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Title | Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-55511118 | ||||||||||||
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Function / homology | ![]() Phase 2 - plateau phase / Phase 0 - rapid depolarisation / Cargo concentration in the ER / cellular response to amine stimulus / axonal spine / COPII-mediated vesicle transport / positive regulation of membrane potential / cellular response to ammonium ion / neurotransmitter receptor transport, postsynaptic endosome to lysosome / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | ||||||||||||
Biological species | ![]() ![]() ![]() | ||||||||||||
Method | ![]() ![]() | ||||||||||||
![]() | Zhang D / Lape R / Shaikh S / Kohegyi B / Watson JF / Cais O / Nakagawa T / Greger IH | ||||||||||||
Funding support | ![]() ![]()
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![]() | ![]() Title: Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics. Authors: Danyang Zhang / Remigijus Lape / Saher A Shaikh / Bianka K Kohegyi / Jake F Watson / Ondrej Cais / Terunaga Nakagawa / Ingo H Greger / ![]() ![]() ![]() Abstract: AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an ...AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse ligands. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we also demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators. | ||||||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 6.8 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 21.8 KB 21.8 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 11.3 KB | Display | ![]() |
Images | ![]() | 147.4 KB | ||
Others | ![]() ![]() ![]() | 4.7 MB 96.9 MB 96.9 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8aymMC ![]() 8aylC ![]() 8aynC ![]() 8ayoC 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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Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 1.07 Å | ||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Additional map: #1
File | emd_15716_additional_1.map | ||||||||||||
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Density Histograms |
-Half map: #2
File | emd_15716_half_map_1.map | ||||||||||||
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Density Histograms |
-Half map: #1
File | emd_15716_half_map_2.map | ||||||||||||
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Density Histograms |
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Sample components
-Entire : GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JN...
Entire | Name: GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-55511118 |
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Components |
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-Supramolecule #1: GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JN...
Supramolecule | Name: GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-55511118 type: complex / ID: 1 / Chimera: Yes / Parent: 0 / Macromolecule list: #1-#3 |
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Source (natural) | Organism: ![]() ![]() ![]() |
-Macromolecule #1: Voltage-dependent calcium channel gamma-8 subunit
Macromolecule | Name: Voltage-dependent calcium channel gamma-8 subunit / type: protein_or_peptide / ID: 1 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() ![]() |
Molecular weight | Theoretical: 43.576004 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: GESLKRWNEE RGLWCEKGVQ VLLTTIGAFA AFGLMTIAIS TDYWLYTRAL ICNTTNLTAG DDGPPHRGGS GSSEKKDPGG LTHSGLWRI CCLEGLKRGV CVKINHFPED TDYDHDSAEY LLRVVRASSI FPILSAILLL LGGVCVAASR VYKSKRNIIL G AGILFVAA ...String: GESLKRWNEE RGLWCEKGVQ VLLTTIGAFA AFGLMTIAIS TDYWLYTRAL ICNTTNLTAG DDGPPHRGGS GSSEKKDPGG LTHSGLWRI CCLEGLKRGV CVKINHFPED TDYDHDSAEY LLRVVRASSI FPILSAILLL LGGVCVAASR VYKSKRNIIL G AGILFVAA GLSNIIGVIV YISANAGEPG PKRDEEKKNH YSYGWSFYFG GLSFILAEVI GVLAVNIYIE RSREAHCQSR SD LLKAGGG AGGSGGSGPS AILRLPSYRF RYRRRSRSSS RGSSEASPSR DASPGGPGGP GFASTDISMY TLSRDPSKGS VAA GLASAG GGGGGAGVGA YGGAAGAAGG GGTGSERDRG SSAGFLTLHN AFPKEAASGV TVTVTGPPAA PAPAPPAPAA PAPG TLSKE AAASNTNTLN RKLEVLFQ |
-Macromolecule #2: Isoform Flip of Glutamate receptor 1
Macromolecule | Name: Isoform Flip of Glutamate receptor 1 / type: protein_or_peptide / ID: 2 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() ![]() |
Molecular weight | Theoretical: 102.66193 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MPYIFAFFCT GFLGAVVGAD YKDDDDKNFP NNIQIGGLFP NQQSQEHAAF RFALSQLTEP PKLLPQIDIV NISDSFEMTY RFCSQFSKG VYAIFGFYER RTVNMLTSFC GALHVCFITP SFPVDTSNQF VLQLRPELQE ALISIIDHYK WQTFVYIYDA D RGLSVLQR ...String: MPYIFAFFCT GFLGAVVGAD YKDDDDKNFP NNIQIGGLFP NQQSQEHAAF RFALSQLTEP PKLLPQIDIV NISDSFEMTY RFCSQFSKG VYAIFGFYER RTVNMLTSFC GALHVCFITP SFPVDTSNQF VLQLRPELQE ALISIIDHYK WQTFVYIYDA D RGLSVLQR VLDTAAEKNW QVTAVNILTT TEEGYRMLFQ DLEKKKERLV VVDCESERLN AILGQIVKLE KNGIGYHYIL AN LGFMDID LNKFKESGAN VTGFQLVNYT DTIPARIMQQ WRTSDSRDHT RVDWKRPKYT SALTYDGVKV MAEAFQSLRR QRI DISRRG NAGDCLANPA VPWGQGIDIQ RALQQVRFEG LTGNVQFNEK GRRTNYTLHV IEMKHDGIRK IGYWNEDDKF VPAA TDAQA GGDNSSVQNR TYIVTTILED PYVMLKKNAN QFEGNDRYEG YCVELAAEIA KHVGYSYRLE IVSDGKYGAR DPDTK AWNG MVGELVYGRA DVAVAPLTIT LVREEVIDFS KPFMSLGISI MIKKPQKSKP GVFSFLDPLA YEIWMCIVFA YIGVSV VLF LVSRFSPYEW HSEEFEEGRD QTTSDQSNEF GIFNSLWFSL GAFMQQGCDI SPRSLSGRIV GGVWWFFTLI IISSYTA NL AAFLTVERMV SPIESAEDLA KQTEIAYGTL EAGSTKEFFR RSKIAVFEKM WTYMKSAEPS VFVRTTEEGM IRVRKSKG K YAYLLESTMN EYIEQRKPCD TMKVGGNLDS KGYGIATPKG SALRGPVNLA VLKLSEQGVL DKLKSKWWYD KGECGSKDS GSKDKTSALS LSNVAGVFYI LIGGLGLAML VALIEFCYKS RSESKRMKGF CLIPQQSINE AIRTSTLPRN SGAGASGGGG SGENGRVVS QDFPKSMQSI PCMSHSSGMP LGATGL |
-Macromolecule #3: Isoform Flip of Glutamate receptor 2
Macromolecule | Name: Isoform Flip of Glutamate receptor 2 / type: protein_or_peptide / ID: 3 / Number of copies: 2 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() ![]() |
Molecular weight | Theoretical: 96.247055 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MQKIMHISVL LSPVLWGLIF GVSSNSIQIG GLFPRGADQE YSAFRVGMVQ FSTSEFRLTP HIDNLEVANS FAVTNAFCSQ FSRGVYAIF GFYDKKSVNT ITSFCGTLHV SFITPSFPTD GTHPFVIQMR PDLKGALLSL IEYYQWDKFA YLYDSDRGLS T LQAVLDSA ...String: MQKIMHISVL LSPVLWGLIF GVSSNSIQIG GLFPRGADQE YSAFRVGMVQ FSTSEFRLTP HIDNLEVANS FAVTNAFCSQ FSRGVYAIF GFYDKKSVNT ITSFCGTLHV SFITPSFPTD GTHPFVIQMR PDLKGALLSL IEYYQWDKFA YLYDSDRGLS T LQAVLDSA AEKKWQVTAI NVGNINNDKK DETYRSLFQD LELKKERRVI LDCERDKVND IVDQVITIGK HVKGYHYIIA NL GFTDGDL LKIQFGGANV SGFQIVDYDD SLVSKFIERW STLEEKEYPG AHTATIKYTS ALTYDAVQVM TEAFRNLRKQ RIE ISRRGN AGDCLANPAV PWGQGVEIER ALKQVQVEGL SGNIKFDQNG KRINYTINIM ELKTNGPRKI GYWSEVDKMV VTLT ELPSG NDTSGLENKT VVVTTILESP YVMMKKNHEM LEGNERYEGY CVDLAAEIAK HCGFKYKLTI VGDGKYGARD ADTKI WNGM VGELVYGKAD IAIAPLTITL VREEVIDFSK PFMSLGISIM IKKPQKSKPG VFSFLDPLAY EIWMCIVFAY IGVSVV LFL VSRFSPYEWH TEEFEDGRET QSSESTNEFG IFNSLWFSLG AFMRQGCDIS PRSLSGRIVG GVWWFFTLII ISSYTAN LA AFLTVERMVS PIESAEDLSK QTEIAYGTLD SGSTKEFFRR SKIAVFDKMW TYMRSAEPSV FVRTTAEGVA RVRKSKGK Y AYLLESTMNE YIEQRKPCDT MKVGGNLDSK GYGIATPKGS SLGTPVNLAV LKLSEQGVLD KLKNKWWYDK GECGAKDSG SKEKTSALSL SNVAGVFYIL VGGLGLAMLV ALIEFCYKSR AEAKRMKVAK NPQNINPSSS |
-Macromolecule #4: 6-[2-chloro-6-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-ol
Macromolecule | Name: 6-[2-chloro-6-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-ol type: ligand / ID: 4 / Number of copies: 2 / Formula: XVD |
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Molecular weight | Theoretical: 328.674 Da |
Chemical component information | ![]() ChemComp-XVD: |
-Macromolecule #5: PALMITIC ACID
Macromolecule | Name: PALMITIC ACID / type: ligand / ID: 5 / Number of copies: 14 / Formula: PLM |
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Molecular weight | Theoretical: 256.424 Da |
Chemical component information | ![]() ChemComp-PLM: |
-Macromolecule #6: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquino...
Macromolecule | Name: {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid type: ligand / ID: 6 / Number of copies: 4 / Formula: ZK1 |
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Molecular weight | Theoretical: 409.254 Da |
Chemical component information | ![]() ChemComp-ZK1: |
-Macromolecule #7: (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: 7 / Number of copies: 6 / Formula: POV |
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Molecular weight | Theoretical: 760.076 Da |
Chemical component information | ![]() ChemComp-POV: |
-Macromolecule #8: (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate
Macromolecule | Name: (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / type: ligand / ID: 8 / Number of copies: 2 / Formula: OLC |
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Molecular weight | Theoretical: 356.54 Da |
Chemical component information | ![]() ChemComp-OLC: |
-Experimental details
-Structure determination
Method | ![]() |
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Aggregation state | particle |
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Sample preparation
Buffer | pH: 8 |
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Vitrification | Cryogen name: ETHANE |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |