+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 7pqt | ||||||
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タイトル | Apo human Kv3.1 cryo-EM structure | ||||||
要素 | Potassium voltage-gated channel subfamily C member 1 | ||||||
キーワード | MEMBRANE PROTEIN / Potassium ion channel / voltage gated / drug target | ||||||
機能・相同性 | 機能・相同性情報 response to nerve growth factor / globus pallidus development / response to potassium ion / response to fibroblast growth factor / response to auditory stimulus / corpus callosum development / positive regulation of potassium ion transmembrane transport / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / response to light intensity / Voltage gated Potassium channels ...response to nerve growth factor / globus pallidus development / response to potassium ion / response to fibroblast growth factor / response to auditory stimulus / corpus callosum development / positive regulation of potassium ion transmembrane transport / voltage-gated monoatomic ion channel activity involved in regulation of presynaptic membrane potential / response to light intensity / Voltage gated Potassium channels / delayed rectifier potassium channel activity / optic nerve development / neuronal cell body membrane / response to amine / voltage-gated potassium channel activity / action potential / kinesin binding / calyx of Held / axolemma / axon terminus / voltage-gated potassium channel complex / potassium ion transmembrane transport / dendrite membrane / potassium ion transport / cerebellum development / protein tetramerization / protein homooligomerization / response to toxic substance / cellular response to xenobiotic stimulus / presynaptic membrane / postsynaptic membrane / transmembrane transporter binding / cell surface / plasma membrane 類似検索 - 分子機能 | ||||||
生物種 | Homo sapiens (ヒト) | ||||||
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: 2.65 Å | ||||||
データ登録者 | Botte, M. / Huber, S. / Bucher, D. / Klint, J.K. / Rodriguez, D. / Tagmose, L. / Chami, M. / Cheng, R. / Hennig, M. / Abdul Rhaman, W. | ||||||
資金援助 | 1件
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引用 | ジャーナル: PNAS Nexus / 年: 2022 タイトル: Apo and ligand-bound high resolution Cryo-EM structures of the human Kv3.1 channel reveal a novel binding site for positive modulators. 著者: Mathieu Botte / Sophie Huber / Denis Bucher / Julie K Klint / David Rodríguez / Lena Tagmose / Mohamed Chami / Robert Cheng / Michael Hennig / Wassim Abdul Rahman / 要旨: Kv3 ion-channels constitute a class of functionally distinct voltage-gated ion channels characterized by their ability to fire at a high frequency. Several disease relevant mutants, together with ...Kv3 ion-channels constitute a class of functionally distinct voltage-gated ion channels characterized by their ability to fire at a high frequency. Several disease relevant mutants, together with biological data, suggest the importance of this class of ion channels as drug targets for CNS disorders, and several drug discovery efforts have been reported. Despite the increasing interest for this class of ion channels, no structure of a Kv3 channel has been reported yet. We have determined the cryo-EM structure of Kv3.1 at 2.6 Å resolution using full-length wild type protein. When compared to known structures for potassium channels from other classes, a novel domain organization is observed with the cytoplasmic T1 domain, containing a well-resolved Zinc site and displaying a rotation by 35°. This suggests a distinct cytoplasmic regulation mechanism for the Kv3.1 channel. A high resolution structure was obtained for Kv3.1 in complex with a novel positive modulator Lu AG00563. The structure reveals a novel ligand binding site for the Kv class of ion channels located between the voltage sensory domain and the channel pore, a region which constitutes a hotspot for disease causing mutations. The discovery of a novel binding site for a positive modulator of a voltage-gated potassium channel could shed light on the mechanism of action for these small molecule potentiators. This finding could enable structure-based drug design on these targets with high therapeutic potential for the treatment of multiple CNS disorders. | ||||||
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 | 7pqt.cif.gz | 245.8 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb7pqt.ent.gz | 192.4 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 7pqt.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 | 7pqt_validation.pdf.gz | 723.1 KB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 7pqt_full_validation.pdf.gz | 750.8 KB | 表示 | |
XML形式データ | 7pqt_validation.xml.gz | 40.2 KB | 表示 | |
CIF形式データ | 7pqt_validation.cif.gz | 61 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/pq/7pqt ftp://data.pdbj.org/pub/pdb/validation_reports/pq/7pqt | HTTPS FTP |
-関連構造データ
関連構造データ | 13604MC 7pquC 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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-要素
#1: タンパク質 | 分子量: 58883.180 Da / 分子数: 4 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: KCNC1 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: P48547 #2: 化合物 | ChemComp-K / #3: 水 | ChemComp-HOH / | 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: Detergent solubilized tetramer of human Kv3.1 potassium ion channel タイプ: COMPLEX / Entity ID: #1 / 由来: RECOMBINANT |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Homo sapiens (ヒト) |
緩衝液 | pH: 7.5 |
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 |
-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: OTHER |
電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2500 nm / 最小 デフォーカス(公称値): 800 nm |
撮影 | 電子線照射量: 70 e/Å2 フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
-解析
CTF補正 | タイプ: PHASE FLIPPING ONLY |
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3次元再構成 | 解像度: 2.65 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 362349 / 対称性のタイプ: POINT |