登録情報 データベース : EMDB / ID : EMD-15716 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 マップデータ 詳細 試料複合体 : GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-55511118タンパク質・ペプチド : Voltage-dependent calcium channel gamma-8 subunitタンパク質・ペプチド : Isoform Flip of Glutamate receptor 1タンパク質・ペプチド : Isoform Flip of Glutamate receptor 2リガンド : 6-[2-chloro-6-(trifluoromethoxy)phenyl]-1H-benzimidazol-2-olリガンド : PALMITIC ACIDリガンド : {[7-morpholin-4-yl-2,3-dioxo-6-(trifluoromethyl)-3,4-dihydroquinoxalin-1(2H)-yl]methyl}phosphonic acidリガンド : (2S)-3-(hexadecanoyloxy)-2-[(9Z)-octadec-9-enoyloxy]propyl 2-(trimethylammonio)ethyl phosphateリガンド : (2R)-2,3-dihydroxypropyl (9Z)-octadec-9-enoate 残り2件を表示 表示を減らす 詳細 キーワード AMPAR / ion channels / neurotransmission / MEMBRANE PROTEIN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 0 - rapid depolarisation / Phase 2 - plateau phase / Cargo concentration in the ER / axonal spine / positive regulation of locomotion involved in locomotory behavior / positive regulation of membrane potential / COPII-mediated vesicle transport / cellular response to ammonium ion / response to sucrose / L-type voltage-gated calcium channel complex ... Phase 0 - rapid depolarisation / Phase 2 - plateau phase / Cargo concentration in the ER / axonal spine / positive regulation of locomotion involved in locomotory behavior / positive regulation of membrane potential / COPII-mediated vesicle transport / cellular response to ammonium ion / response to sucrose / L-type voltage-gated calcium channel complex / postsynaptic neurotransmitter receptor diffusion trapping / neuron spine / myosin V binding / Trafficking of AMPA receptors / channel regulator activity / regulation of AMPA receptor activity / LGI-ADAM interactions / proximal dendrite / regulation of monoatomic ion transmembrane transport / protein phosphatase 2B binding / response to arsenic-containing substance / cellular response to dsRNA / cellular response to L-glutamate / dendritic spine membrane / long-term synaptic depression / Synaptic adhesion-like molecules / beta-2 adrenergic receptor binding / cellular response to peptide hormone stimulus / response to morphine / neuronal cell body membrane / spine synapse / dendritic spine neck / protein kinase A binding / dendritic spine head / peptide hormone receptor binding / cellular response to amine stimulus / response to psychosocial stress / spinal cord development / Activation of AMPA receptors / perisynaptic space / ligand-gated monoatomic cation channel activity / AMPA glutamate receptor activity / transmission of nerve impulse / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / behavioral response to pain / kainate selective glutamate receptor activity / AMPA glutamate receptor complex / cellular response to glycine / extracellularly glutamate-gated ion channel activity / adenylate cyclase binding / ionotropic glutamate receptor complex / immunoglobulin binding / asymmetric synapse / conditioned place preference / excitatory synapse / response to electrical stimulus / regulation of receptor recycling / G-protein alpha-subunit binding / positive regulation of excitatory postsynaptic potential / glutamate receptor binding / Unblocking of NMDA receptors, glutamate binding and activation / long-term memory / positive regulation of synaptic transmission / positive regulation of synaptic transmission, glutamatergic / postsynaptic density, intracellular component / regulation of postsynaptic membrane neurotransmitter receptor levels / neuronal action potential / voltage-gated calcium channel activity / regulation of synaptic transmission, glutamatergic / response to fungicide / glutamate-gated receptor activity / cytoskeletal protein binding / synapse assembly / regulation of long-term synaptic depression / extracellular ligand-gated monoatomic ion channel activity / cellular response to brain-derived neurotrophic factor stimulus / glutamate-gated calcium ion channel activity / presynaptic active zone membrane / somatodendritic compartment / ionotropic glutamate receptor binding / dendrite membrane / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / dendrite cytoplasm / ionotropic glutamate receptor signaling pathway / synaptic membrane / SNARE binding / dendritic shaft / calcium channel regulator activity / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / response to cocaine / synaptic transmission, glutamatergic / PDZ domain binding / protein tetramerization / cellular response to amino acid stimulus / neuromuscular junction / response to nutrient levels / establishment of protein localization / response to peptide hormone / postsynaptic density membrane 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 / 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 ... 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 / 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 類似検索 - ドメイン・相同性 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 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 JF / Cais O / Nakagawa T / Greger IH 資金援助 英国, 米国, 3件 詳細 詳細を隠すOrganization Grant number 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 - ヘッダ(付随情報) 公開 2023年4月19日 - マップ公開 2023年4月19日 - 更新 2024年11月6日 - 現状 2024年11月6日 処理サイト : PDBe / 状態 : 公開
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