+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8fwu | |||||||||
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タイトル | Structure of the ligand-binding and transmembrane domains of kainate receptor GluK2 in complex with the positive allosteric modulator BPAM344 and competitive antagonist DNQX | |||||||||
要素 | Glutamate receptor ionotropic, kainate 2 | |||||||||
キーワード | MEMBRANE PROTEIN / iGluR / Kainate receptor / positive allosteric modulator / DNQX | |||||||||
機能・相同性 | 機能・相同性情報 mossy fiber rosette / detection of cold stimulus involved in thermoception / Activation of Na-permeable kainate receptors / kainate selective glutamate receptor complex / Activation of Ca-permeable Kainate Receptor / negative regulation of synaptic transmission, glutamatergic / regulation of short-term neuronal synaptic plasticity / inhibitory postsynaptic potential / glutamate receptor activity / ubiquitin conjugating enzyme binding ...mossy fiber rosette / detection of cold stimulus involved in thermoception / Activation of Na-permeable kainate receptors / kainate selective glutamate receptor complex / Activation of Ca-permeable Kainate Receptor / negative regulation of synaptic transmission, glutamatergic / regulation of short-term neuronal synaptic plasticity / inhibitory postsynaptic potential / glutamate receptor activity / ubiquitin conjugating enzyme binding / receptor clustering / modulation of excitatory postsynaptic potential / extracellularly glutamate-gated ion channel activity / regulation of JNK cascade / kainate selective glutamate receptor activity / ionotropic glutamate receptor complex / behavioral fear response / neuronal action potential / positive regulation of synaptic transmission / glutamate-gated receptor activity / glutamate-gated calcium ion channel activity / ligand-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / presynaptic modulation of chemical synaptic transmission / dendrite cytoplasm / hippocampal mossy fiber to CA3 synapse / regulation of membrane potential / excitatory postsynaptic potential / SNARE binding / synaptic transmission, glutamatergic / transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential / PDZ domain binding / postsynaptic density membrane / regulation of long-term neuronal synaptic plasticity / modulation of chemical synaptic transmission / terminal bouton / intracellular calcium ion homeostasis / positive regulation of neuron apoptotic process / presynaptic membrane / scaffold protein binding / chemical synaptic transmission / perikaryon / postsynaptic membrane / neuron apoptotic process / negative regulation of neuron apoptotic process / postsynaptic density / axon / neuronal cell body / glutamatergic synapse / ubiquitin protein ligase binding / dendrite / synapse / identical protein binding / membrane / plasma membrane 類似検索 - 分子機能 | |||||||||
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: 3.18 Å | |||||||||
データ登録者 | Yen, L.Y. / Gangwar, S.P. / Yelshanskaya, M.V. / Sobolevsky, A.I. | |||||||||
資金援助 | 米国, 2件
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引用 | ジャーナル: Cell Rep / 年: 2023 タイトル: Positive and negative allosteric modulation of GluK2 kainate receptors by BPAM344 and antiepileptic perampanel. 著者: Shanti Pal Gangwar / Laura Y Yen / Maria V Yelshanskaya / Alexander I Sobolevsky / 要旨: Kainate receptors (KARs) are a subtype of ionotropic glutamate receptors that control synaptic transmission in the central nervous system and are implicated in neurological, psychiatric, and ...Kainate receptors (KARs) are a subtype of ionotropic glutamate receptors that control synaptic transmission in the central nervous system and are implicated in neurological, psychiatric, and neurodevelopmental disorders. Understanding the regulation of KAR function by small molecules is essential for exploring these receptors as drug targets. Here, we present cryoelectron microscopy (cryo-EM) structures of KAR GluK2 in complex with the positive allosteric modulator BPAM344, competitive antagonist DNQX, and negative allosteric modulator, antiepileptic drug perampanel. Our structures show that two BPAM344 molecules bind per ligand-binding domain dimer interface. In the absence of an agonist or in the presence of DNQX, BPAM344 stabilizes GluK2 in the closed state. The closed state is also stabilized by perampanel, which binds to the ion channel extracellular collar sites located in two out of four GluK2 subunits. The molecular mechanisms of positive and negative allosteric modulation of KAR provide a guide for developing new therapeutic strategies. | |||||||||
履歴 |
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-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
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-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 8fwu.cif.gz | 351.4 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8fwu.ent.gz | 278.5 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8fwu.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 8fwu_validation.pdf.gz | 2.3 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 8fwu_full_validation.pdf.gz | 2.4 MB | 表示 | |
XML形式データ | 8fwu_validation.xml.gz | 82.4 KB | 表示 | |
CIF形式データ | 8fwu_validation.cif.gz | 111 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/fw/8fwu ftp://data.pdbj.org/pub/pdb/validation_reports/fw/8fwu | HTTPS FTP |
-関連構造データ
関連構造データ | 29519MC 8fwqC 8fwrC 8fwsC 8fwtC 8fwvC 8fwwC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-リンク
-集合体
登録構造単位 |
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1 |
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-要素
-タンパク質 , 1種, 4分子 ABCD
#1: タンパク質 | 分子量: 102509.977 Da / 分子数: 4 / 由来タイプ: 組換発現 / 由来: (組換発現) Rattus norvegicus (ドブネズミ) / 遺伝子: Grik2, Glur6 / プラスミド: pEG BacMam / 細胞株 (発現宿主): HEK / 器官 (発現宿主): Kidney / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: P42260 |
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-糖 , 3種, 8分子
#2: 多糖 | 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose #3: 多糖 | #6: 糖 | |
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-非ポリマー , 6種, 40分子
#4: 化合物 | ChemComp-DNQ / #5: 化合物 | ChemComp-POV / ( #7: 化合物 | ChemComp-NA / #8: 化合物 | #9: 化合物 | ChemComp-2J9 / #10: 水 | ChemComp-HOH / | |
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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 |
-試料調製
構成要素 | 名称: GluK2 / タイプ: COMPLEX 詳細: Map displaying ligand binding and transmembrane domain Entity ID: #1 / 由来: RECOMBINANT | ||||||||||||||||||||
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分子量 | 実験値: NO | ||||||||||||||||||||
由来(天然) | 生物種: Rattus norvegicus (ドブネズミ) | ||||||||||||||||||||
由来(組換発現) | 生物種: Homo sapiens (ヒト) | ||||||||||||||||||||
緩衝液 | pH: 8 | ||||||||||||||||||||
緩衝液成分 |
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試料 | 濃度: 5 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES 詳細: Protein extracted and reconstituted in a detergent micelle | ||||||||||||||||||||
試料支持 | グリッドのタイプ: Quantifoil R1.2/1.3 | ||||||||||||||||||||
急速凍結 | 装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE / 湿度: 100 % / 凍結前の試料温度: 277 K |
-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: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: SPOT SCAN |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2000 nm / 最小 デフォーカス(公称値): 1000 nm |
撮影 | 電子線照射量: 57.9 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
-解析
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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3次元再構成 | 解像度: 3.18 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 135549 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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