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基本情報
登録情報 | データベース: PDB / ID: 8ayl | ||||||||||||
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タイトル | Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-61432059 | ||||||||||||
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![]() | MEMBRANE PROTEIN / AMPAR / ion channels / neurotransmission | ||||||||||||
機能・相同性 | ![]() 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 / neurotransmitter receptor activity involved in regulation of postsynaptic cytosolic calcium ion concentration / LGI-ADAM interactions / myosin V binding / Trafficking of AMPA receptors / regulation of AMPA receptor activity / neuron spine / neurotransmitter receptor internalization / channel regulator activity / protein phosphatase 2B binding / response to arsenic-containing substance / cellular response to dsRNA / postsynaptic neurotransmitter receptor diffusion trapping / dendritic spine membrane / Synaptic adhesion-like molecules / glutamate-gated calcium ion channel activity / long-term synaptic depression / cellular response to peptide hormone stimulus / protein kinase A binding / spinal cord development / neuronal cell body membrane / spine synapse / dendritic spine neck / dendritic spine head / Activation of AMPA receptors / perisynaptic space / transmission of nerve impulse / AMPA glutamate receptor activity / regulation of postsynaptic membrane neurotransmitter receptor levels / Trafficking of GluR2-containing AMPA receptors / response to lithium ion / immunoglobulin binding / AMPA glutamate receptor complex / adenylate cyclase binding / kainate selective glutamate receptor activity / cellular response to organic cyclic compound / ionotropic glutamate receptor complex / extracellularly glutamate-gated ion channel activity / cellular response to glycine / excitatory synapse / calcium channel regulator activity / asymmetric synapse / G-protein alpha-subunit binding / regulation of receptor recycling / voltage-gated calcium channel activity / neuronal action potential / Unblocking of NMDA receptors, glutamate binding and activation / regulation of postsynaptic membrane potential / postsynaptic density, intracellular component / glutamate receptor binding / positive regulation of synaptic transmission / long-term memory / response to electrical stimulus / glutamate-gated receptor activity / presynaptic active zone membrane / beta-2 adrenergic receptor binding / response to fungicide / regulation of synaptic transmission, glutamatergic / somatodendritic compartment / cellular response to brain-derived neurotrophic factor stimulus / dendrite membrane / synapse assembly / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / cytoskeletal protein binding / ionotropic glutamate receptor signaling pathway / dendrite cytoplasm / positive regulation of synaptic transmission, glutamatergic / SNARE binding / response to cocaine / dendritic shaft / synaptic membrane / synaptic transmission, glutamatergic / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / PDZ domain binding / long-term synaptic potentiation / protein tetramerization / cellular response to amino acid stimulus / postsynaptic density membrane / ionotropic glutamate receptor binding / Schaffer collateral - CA1 synapse / modulation of chemical synaptic transmission / regulation of synaptic plasticity / establishment of protein localization / neuromuscular junction / response to organic cyclic compound / receptor internalization / terminal bouton / recycling endosome / response to toxic substance / cerebral cortex development / cellular response to growth factor stimulus 類似検索 - 分子機能 | ||||||||||||
生物種 | ![]() ![]() | ||||||||||||
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: 3.2 Å | ||||||||||||
![]() | Zhang, D. / Lape, R. / Shaikh, S. / Kohegyi, B. / Watson, J.F. / Cais, O. / Nakagawa, T. / Greger, I. | ||||||||||||
資金援助 | ![]() ![]()
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![]() | ![]() 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 |
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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ダウンロード
PDBx/mmCIF形式 | ![]() | 703.7 KB | 表示 | ![]() |
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PDB形式 | ![]() | 559.4 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 1.9 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.9 MB | 表示 | |
XML形式データ | ![]() | 79.8 KB | 表示 | |
CIF形式データ | ![]() | 107.9 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
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リンク
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集合体
登録構造単位 | ![]()
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非結晶学的対称性 (NCS) | NCSドメイン:
NCSドメイン領域:
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), ベクター: |
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要素
-Isoform Flip of Glutamate receptor ... , 2種, 4分子 BDAC
#1: タンパク質 | 分子量: 96247.055 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() #3: タンパク質 | 分子量: 102661.930 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
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-タンパク質 , 1種, 2分子 JI
#2: タンパク質 | 分子量: 43576.004 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
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-非ポリマー , 5種, 24分子 ![](data/chem/img/ZK1.gif)
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#4: 化合物 | ChemComp-ZK1 / {[ #5: 化合物 | ChemComp-OLC / ( #6: 化合物 | ChemComp-PLM / #7: 化合物 | ChemComp-POV / ( #8: 化合物 | |
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-詳細
研究の焦点であるリガンドがあるか | Y |
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-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
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EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
構成要素 | 名称: Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-61432059 タイプ: COMPLEX / Entity ID: #1-#3 / 由来: RECOMBINANT |
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由来(天然) | 生物種: ![]() ![]() |
由来(組換発現) | 生物種: ![]() |
緩衝液 | pH: 8 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
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電子顕微鏡撮影
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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顕微鏡 | モデル: FEI TITAN KRIOS |
電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 3000 nm / 最小 デフォーカス(公称値): 1200 nm |
試料ホルダ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
撮影 | 電子線照射量: 50 e/Å2 / フィルム・検出器のモデル: GATAN K3 (6k x 4k) |
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解析
ソフトウェア |
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EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3次元再構成 | 解像度: 3.2 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 315406 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
精密化 | 交差検証法: NONE 立体化学のターゲット値: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
原子変位パラメータ | Biso mean: 51.41 Å2 | ||||||||||||||||||||||||
拘束条件 |
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Refine LS restraints NCS | タイプ: NCS constraints / Rms dev position: 0.00069860284038 Å |