登録情報 データベース : PDB / ID : 8aym 構造の表示 ダウンロードとリンクタイトル Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-55511118 要素(Isoform Flip of Glutamate receptor ...) x 2 Voltage-dependent calcium channel gamma-8 subunit 詳細キーワード MEMBRANE PROTEIN / AMPAR / ion channels / neurotransmission機能・相同性 機能・相同性情報分子機能 ドメイン・相同性 構成要素
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 / L-type voltage-gated calcium channel complex ... 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 / L-type voltage-gated calcium channel complex / LGI-ADAM interactions / myosin V binding / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / Trafficking of AMPA receptors / neuron spine / regulation of AMPA receptor activity / protein phosphatase 2B binding / neurotransmitter receptor internalization / response to arsenic-containing substance / cellular response to dsRNA / postsynaptic neurotransmitter receptor diffusion trapping / dendritic spine membrane / Synaptic adhesion-like molecules / long-term synaptic depression / beta-2 adrenergic receptor binding / cellular response to peptide hormone stimulus / protein kinase A binding / spinal cord development / spine synapse / dendritic spine neck / neuronal cell body membrane / dendritic spine head / Activation of AMPA receptors / perisynaptic space / transmission of nerve impulse / AMPA glutamate receptor activity / channel regulator activity / ligand-gated monoatomic cation channel activity / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / regulation of postsynaptic membrane neurotransmitter receptor levels / immunoglobulin binding / AMPA glutamate receptor complex / adenylate cyclase binding / kainate selective glutamate receptor activity / cellular response to organic cyclic compound / ionotropic glutamate receptor complex / excitatory synapse / extracellularly glutamate-gated ion channel activity / neuronal action potential / cellular response to glycine / calcium channel regulator activity / asymmetric synapse / G-protein alpha-subunit binding / regulation of receptor recycling / voltage-gated calcium channel activity / regulation of postsynaptic membrane potential / Unblocking of NMDA receptors, glutamate binding and activation / postsynaptic density, intracellular component / positive regulation of synaptic transmission / glutamate receptor binding / long-term memory / extracellular ligand-gated monoatomic ion channel activity / positive regulation of synaptic transmission, glutamatergic / response to electrical stimulus / glutamate-gated receptor activity / glutamate-gated calcium ion channel activity / presynaptic active zone membrane / response to fungicide / regulation of synaptic transmission, glutamatergic / somatodendritic compartment / synapse assembly / cellular response to brain-derived neurotrophic factor stimulus / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / cytoskeletal protein binding / ionotropic glutamate receptor binding / dendrite cytoplasm / ionotropic glutamate receptor signaling pathway / cellular response to amino acid stimulus / SNARE binding / response to cocaine / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / dendritic shaft / synaptic membrane / synaptic transmission, glutamatergic / PDZ domain binding / long-term synaptic potentiation / protein tetramerization / postsynaptic density membrane / modulation of chemical synaptic transmission / establishment of protein localization / neuromuscular junction / regulation of synaptic plasticity / Schaffer collateral - CA1 synapse / terminal bouton / response to organic cyclic compound / receptor internalization / recycling endosome / response to toxic substance 類似検索 - 分子機能 Voltage-dependent calcium channel, gamma-8 subunit / : / PMP-22/EMP/MP20/Claudin family / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily / Bacterial extracellular solute-binding proteins, family 3 / Solute-binding protein family 3/N-terminal domain of MltF / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / : ... Voltage-dependent calcium channel, gamma-8 subunit / : / PMP-22/EMP/MP20/Claudin family / Voltage-dependent calcium channel, gamma subunit / PMP-22/EMP/MP20/Claudin superfamily / Bacterial extracellular solute-binding proteins, family 3 / Solute-binding protein family 3/N-terminal domain of MltF / Ionotropic glutamate receptor, metazoa / Ligated ion channel L-glutamate- and glycine-binding site / : / Ligand-gated ion channel / Ionotropic glutamate receptor, L-glutamate and glycine-binding domain / Ligated ion channel L-glutamate- and glycine-binding site / 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 類似検索 - ドメイン・相同性 (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate / PALMITIC ACID / Chem-POV / Chem-XVD / Chem-ZK1 / Glutamate receptor 1 / Glutamate receptor 2 / Voltage-dependent calcium channel gamma-8 subunit 類似検索 - 構成要素生物種 Rattus norvegicus (ドブネズミ)手法 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 3.3 Å 詳細データ登録者 Zhang, D. / Lape, R. / Shaikh, S. / Kohegyi, B. / Watson, J.F. / Cais, O. / Nakagawa, T. / Greger, I.H. 資金援助 英国, 米国, 3件 詳細 詳細を隠す組織 認可番号 国 Medical Research Council (MRC, United Kingdom) MRU105174197 英国 Wellcome Trust 223194/Z/21/Z National Institutes of Health/National Institute of Mental Health (NIH/NIMH) R56/R01MH123474 米国
引用ジャーナル : Nat Commun / 年 : 2023タイトル : Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics.著者 : Danyang Zhang / Remigijus Lape / Saher A Shaikh / Bianka K Kohegyi / Jake F Watson / Ondrej Cais / Terunaga Nakagawa / Ingo H Greger / 要旨 : 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. 履歴 登録 2022年9月2日 登録サイト : PDBE / 処理サイト : PDBE改定 1.0 2023年4月19日 Provider : repository / タイプ : Initial release