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- PDB-8ayl: Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8... -

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Basic information

Entry
Database: PDB / ID: 8ayl
TitleResting state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-61432059
Components
  • (Isoform Flip of Glutamate receptor ...) x 2
  • Voltage-dependent calcium channel gamma-8 subunit
KeywordsMEMBRANE PROTEIN / AMPAR / ion channels / neurotransmission
Function / homology
Function and homology information


Phase 0 - rapid depolarisation / Phase 2 - plateau phase / Cargo concentration in the ER / cellular response to amine stimulus / axonal spine / COPII-mediated vesicle transport / positive regulation of membrane potential / positive regulation of locomotion involved in locomotory behavior / cellular response to ammonium ion / response to sucrose ...Phase 0 - rapid depolarisation / Phase 2 - plateau phase / Cargo concentration in the ER / cellular response to amine stimulus / axonal spine / COPII-mediated vesicle transport / positive regulation of membrane potential / positive regulation of locomotion involved in locomotory behavior / cellular response to ammonium ion / response to sucrose / L-type voltage-gated calcium channel complex / LGI-ADAM interactions / postsynaptic neurotransmitter receptor diffusion trapping / proximal dendrite / myosin V binding / neuron spine / Trafficking of AMPA receptors / channel regulator activity / cellular response to L-glutamate / regulation of AMPA receptor activity / protein phosphatase 2B binding / regulation of monoatomic ion transmembrane transport / conditioned place preference / response to arsenic-containing substance / cellular response to dsRNA / dendritic spine membrane / Synaptic adhesion-like molecules / long-term synaptic depression / beta-2 adrenergic receptor binding / cellular response to peptide hormone stimulus / response to morphine / neuronal cell body membrane / peptide hormone receptor binding / protein kinase A binding / spine synapse / dendritic spine neck / response to psychosocial stress / dendritic spine head / spinal cord development / Activation of AMPA receptors / perisynaptic space / AMPA glutamate receptor activity / transmission of nerve impulse / ligand-gated monoatomic cation channel activity / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / immunoglobulin binding / : / behavioral response to pain / AMPA glutamate receptor complex / kainate selective glutamate receptor activity / ionotropic glutamate receptor complex / cellular response to glycine / extracellularly glutamate-gated ion channel activity / adenylate cyclase binding / excitatory synapse / positive regulation of excitatory postsynaptic potential / asymmetric synapse / regulation of receptor recycling / Unblocking of NMDA receptors, glutamate binding and activation / G-protein alpha-subunit binding / long-term memory / positive regulation of synaptic transmission / postsynaptic density, intracellular component / glutamate receptor binding / regulation of postsynaptic membrane neurotransmitter receptor levels / voltage-gated calcium channel activity / neuronal action potential / response to electrical stimulus / glutamate-gated receptor activity / regulation of synaptic transmission, glutamatergic / synapse assembly / response to fungicide / cytoskeletal protein binding / ionotropic glutamate receptor binding / presynaptic active zone membrane / extracellular ligand-gated monoatomic ion channel activity / somatodendritic compartment / glutamate-gated calcium ion channel activity / cellular response to brain-derived neurotrophic factor stimulus / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / dendrite membrane / calcium channel regulator activity / dendrite cytoplasm / ionotropic glutamate receptor signaling pathway / positive regulation of synaptic transmission, glutamatergic / SNARE binding / dendritic shaft / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / synaptic transmission, glutamatergic / PDZ domain binding / protein tetramerization / cellular response to amino acid stimulus / response to cocaine / establishment of protein localization / synaptic membrane / modulation of chemical synaptic transmission / response to nutrient levels / postsynaptic density membrane / terminal bouton
Similarity search - Function
Voltage-dependent calcium channel, gamma-8 subunit / Butyryl-CoA Dehydrogenase, subunit A; domain 3 - #150 / : / PMP-22/EMP/MP20/Claudin family / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily / Butyryl-CoA Dehydrogenase, subunit A; domain 3 / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain ...Voltage-dependent calcium channel, gamma-8 subunit / Butyryl-CoA Dehydrogenase, subunit A; domain 3 - #150 / : / PMP-22/EMP/MP20/Claudin family / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily / Butyryl-CoA Dehydrogenase, subunit A; domain 3 / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / Ligand-gated ion channel / : / Ionotropic glutamate receptor / Eukaryotic homologues of bacterial periplasmic substrate binding proteins. / Receptor, ligand binding region / Receptor family ligand binding region / Periplasmic binding protein-like I / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-OIJ / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / PALMITIC ACID / Chem-POV / Chem-ZK1 / Glutamate receptor 1 / Glutamate receptor 2 / Voltage-dependent calcium channel gamma-8 subunit
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsZhang, D. / Lape, R. / Shaikh, S. / Kohegyi, B. / Watson, J.F. / Cais, O. / Nakagawa, T. / Greger, I.
Funding support United Kingdom, United States, 3items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MRU105174197 United Kingdom
Wellcome Trust223194/Z/21/Z United Kingdom
National Institutes of Health/National Institute of Mental Health (NIH/NIMH)R56/R01MH123474 United States
CitationJournal: Nat Commun / Year: 2023
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
DepositionSep 2, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 19, 2023Provider: repository / Type: Initial release
Revision 1.1May 3, 2023Group: Source and taxonomy / Category: entity_src_gen
Item: _entity_src_gen.gene_src_common_name / _entity_src_gen.pdbx_gene_src_ncbi_taxonomy_id / _entity_src_gen.pdbx_gene_src_scientific_name
Revision 2.0May 24, 2023Group: Non-polymer description / Refinement description / Category: chem_comp / struct_ncs_dom_lim
Item: _chem_comp.formula / _struct_ncs_dom_lim.beg_label_asym_id ..._chem_comp.formula / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id
Revision 2.1Nov 13, 2024Group: Data collection / Refinement description / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / pdbx_entry_details / pdbx_modification_feature / struct_ncs_dom_lim
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification ..._em_admin.last_update / _pdbx_entry_details.has_protein_modification / _struct_ncs_dom_lim.beg_auth_asym_id / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_auth_seq_id / _struct_ncs_dom_lim.end_auth_asym_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Isoform Flip of Glutamate receptor 2
J: Voltage-dependent calcium channel gamma-8 subunit
I: Voltage-dependent calcium channel gamma-8 subunit
A: Isoform Flip of Glutamate receptor 1
D: Isoform Flip of Glutamate receptor 2
C: Isoform Flip of Glutamate receptor 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)495,53230
Polymers484,9706
Non-polymers10,56224
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1chain "J"
d_2ens_1chain "I"

NCS domain segments:

Ens-ID: ens_1

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11GLUGLUHISHISJB16 - 23416 - 234
d_12OIJOIJOIJOIJJK501
d_13PLMPLMPLMPLMAO901
d_21GLUGLUHISHISIC16 - 23416 - 234
d_22OIJOIJOIJOIJIM501
d_23PLMPLMPLMPLMCY901

NCS oper: (Code: givenMatrix: (-0.999999534776, 0.000280959879172, 0.000922772238202), (-0.000281262083838, -0.999999906856, -0.000327383046606), (0.00092268017075, -0.000327642435143, 0.999999520656) ...NCS oper: (Code: given
Matrix: (-0.999999534776, 0.000280959879172, 0.000922772238202), (-0.000281262083838, -0.999999906856, -0.000327383046606), (0.00092268017075, -0.000327642435143, 0.999999520656)
Vector: 132.686188235, 109.176665226, -0.0586976878415)

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Components

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Isoform Flip of Glutamate receptor ... , 2 types, 4 molecules BDAC

#1: Protein Isoform Flip of Glutamate receptor 2 / GluR-2 / AMPA-selective glutamate receptor 2 / GluR-B / GluR-K2 / Glutamate receptor ionotropic / ...GluR-2 / AMPA-selective glutamate receptor 2 / GluR-B / GluR-K2 / Glutamate receptor ionotropic / AMPA 2 / GluA2


Mass: 96247.055 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gria2, Glur2 / Production host: Homo sapiens (human) / References: UniProt: P19491
#3: Protein Isoform Flip of Glutamate receptor 1 / GluR-1 / AMPA-selective glutamate receptor 1 / GluR-A / GluR-K1 / Glutamate receptor ionotropic / ...GluR-1 / AMPA-selective glutamate receptor 1 / GluR-A / GluR-K1 / Glutamate receptor ionotropic / AMPA 1 / GluA1


Mass: 102661.930 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gria1, Glur1 / Production host: Homo sapiens (human) / References: UniProt: P19490

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Protein , 1 types, 2 molecules JI

#2: Protein Voltage-dependent calcium channel gamma-8 subunit / Neuronal voltage-gated calcium channel gamma-8 subunit / Transmembrane AMPAR regulatory protein ...Neuronal voltage-gated calcium channel gamma-8 subunit / Transmembrane AMPAR regulatory protein gamma-8 / TARP gamma-8


Mass: 43576.004 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Cacng8 / Production host: Homo sapiens (human) / References: UniProt: Q8VHW5

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Non-polymers , 5 types, 24 molecules

#4: Chemical
ChemComp-ZK1 / {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acid / [[3,4-Dihydro-7-(4-morpholinyl)-2,3-dioxo-6-(trifluorom ethyl)-1(2H)-quinoxalinyl]methyl]phosphonic acid


Mass: 409.254 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C14H15F3N3O6P / Feature type: SUBJECT OF INVESTIGATION / Comment: antagonist, medication*YM
#5: Chemical
ChemComp-OLC / (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / 1-Oleoyl-R-glycerol


Mass: 356.540 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H40O4 / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical
ChemComp-PLM / PALMITIC ACID


Mass: 256.424 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C16H32O2 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical
ChemComp-POV / (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphate / POPC


Mass: 760.076 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C42H82NO8P / Feature type: SUBJECT OF INVESTIGATION / Comment: phospholipid*YM
#8: Chemical ChemComp-OIJ / 5-[2-(4-fluorophenyl)-7-(4-oxidanylpiperidin-1-yl)pyrazolo[1,5-c]pyrimidin-3-yl]-1,3-dihydroindol-2-one


Mass: 443.473 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H22FN5O2 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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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: Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-61432059
Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT
Source (natural)Organism: Rattus (rat)
Source (recombinant)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 FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1200 nm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

Software
NameVersionClassificationNB
phenix.real_space_refine1.18.2_3874refinement
PHENIX1.18.2_3874refinement
EM software
IDNameVersionCategory
2EPUimage acquisition
9PHENIX1.18.2model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 315406 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 51.41 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.006916028
ELECTRON MICROSCOPYf_angle_d0.600521646
ELECTRON MICROSCOPYf_chiral_restr0.04252408
ELECTRON MICROSCOPYf_plane_restr0.00352624
ELECTRON MICROSCOPYf_dihedral_angle_d13.71662512
Refine LS restraints NCSType: NCS constraints / Rms dev position: 0.00069860284038 Å

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