+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-41261 | |||||||||
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タイトル | Cryo-EM structure of Nav1.7 with RLZ | |||||||||
マップデータ | ||||||||||
試料 |
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キーワード | Cryo-EM / sodium channel / VGSC / Nav1.7 / MEMBRANE PROTEIN | |||||||||
機能・相同性 | 機能・相同性情報 corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / detection of mechanical stimulus involved in sensory perception / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / regulation of sodium ion transmembrane transport ...corticospinal neuron axon guidance / positive regulation of voltage-gated sodium channel activity / response to pyrethroid / detection of mechanical stimulus involved in sensory perception / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / membrane depolarization during Purkinje myocyte cell action potential / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / regulation of sodium ion transmembrane transport / membrane depolarization during cardiac muscle cell action potential / membrane depolarization during action potential / positive regulation of sodium ion transport / node of Ranvier / voltage-gated sodium channel complex / cardiac muscle cell action potential involved in contraction / locomotion / regulation of ventricular cardiac muscle cell membrane repolarization / sodium channel inhibitor activity / neuronal action potential propagation / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / sodium ion transport / Phase 0 - rapid depolarisation / regulation of heart rate by cardiac conduction / detection of temperature stimulus involved in sensory perception of pain / behavioral response to pain / membrane depolarization / intercalated disc / sodium channel regulator activity / sodium ion transmembrane transport / cardiac muscle contraction / sensory perception of pain / T-tubule / post-embryonic development / axon guidance / positive regulation of neuron projection development / Sensory perception of sweet, bitter, and umami (glutamate) taste / response to toxic substance / circadian rhythm / nervous system development / gene expression / response to heat / chemical synaptic transmission / perikaryon / transmembrane transporter binding / cell adhesion / inflammatory response / axon / synapse / extracellular region / plasma membrane 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.9 Å | |||||||||
データ登録者 | Fan X / Huang J / Yan N | |||||||||
資金援助 | フランス, 1件
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引用 | ジャーナル: Proc Natl Acad Sci U S A / 年: 2023 タイトル: Dual-pocket inhibition of Na channels by the antiepileptic drug lamotrigine. 著者: Jian Huang / Xiao Fan / Xueqin Jin / Liming Teng / Nieng Yan / 要旨: Voltage-gated sodium (Na) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na channels serve as the primary targets for several ...Voltage-gated sodium (Na) channels govern membrane excitability, thus setting the foundation for various physiological and neuronal processes. Na channels serve as the primary targets for several classes of widely used and investigational drugs, including local anesthetics, antiepileptic drugs, antiarrhythmics, and analgesics. In this study, we present cryogenic electron microscopy (cryo-EM) structures of human Na1.7 bound to two clinical drugs, riluzole (RLZ) and lamotrigine (LTG), at resolutions of 2.9 Å and 2.7 Å, respectively. A 3D EM reconstruction of ligand-free Na1.7 was also obtained at 2.1 Å resolution. RLZ resides in the central cavity of the pore domain and is coordinated by residues from repeats III and IV. Whereas one LTG molecule also binds to the central cavity, the other is found beneath the intracellular gate, known as site BIG. Therefore, LTG, similar to lacosamide and cannabidiol, blocks Na channels via a dual-pocket mechanism. These structures, complemented with docking and mutational analyses, also explain the structure-activity relationships of the LTG-related linear 6,6 series that have been developed for improved efficacy and subtype specificity on different Na channels. Our findings reveal the molecular basis for these drugs' mechanism of action and will aid the development of novel antiepileptic and pain-relieving drugs. | |||||||||
履歴 |
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-構造の表示
添付画像 |
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-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_41261.map.gz | 59.4 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-41261-v30.xml emd-41261.xml | 20.1 KB 20.1 KB | 表示 表示 | EMDBヘッダ |
FSC (解像度算出) | emd_41261_fsc.xml | 8.4 KB | 表示 | FSCデータファイル |
画像 | emd_41261.png | 49.5 KB | ||
マスクデータ | emd_41261_msk_1.map | 64 MB | マスクマップ | |
Filedesc metadata | emd-41261.cif.gz | 7.6 KB | ||
その他 | emd_41261_half_map_1.map.gz emd_41261_half_map_2.map.gz | 59.3 MB 59.3 MB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-41261 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-41261 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_41261_validation.pdf.gz | 1.1 MB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_41261_full_validation.pdf.gz | 1.1 MB | 表示 | |
XML形式データ | emd_41261_validation.xml.gz | 16.3 KB | 表示 | |
CIF形式データ | emd_41261_validation.cif.gz | 21.4 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-41261 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-41261 | HTTPS FTP |
-関連構造データ
関連構造データ | 8thgMC 8thhC M: このマップから作成された原子モデル 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
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_41261.map.gz / 形式: CCP4 / 大きさ: 64 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 1.036 Å | ||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
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-添付データ
-マスク #1
ファイル | emd_41261_msk_1.map | ||||||||||||
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投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: half map 1
ファイル | emd_41261_half_map_1.map | ||||||||||||
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注釈 | half map 1 | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-ハーフマップ: half map 2
ファイル | emd_41261_half_map_2.map | ||||||||||||
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注釈 | half map 2 | ||||||||||||
投影像・断面図 |
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密度ヒストグラム |
-試料の構成要素
+全体 : Human voltage-gated sodium channel Nav1.7 with beta subunits
+超分子 #1: Human voltage-gated sodium channel Nav1.7 with beta subunits
+分子 #1: Sodium channel protein type 9 subunit alpha
+分子 #2: Sodium channel subunit beta-1
+分子 #3: Sodium channel subunit beta-2
+分子 #5: 2-acetamido-2-deoxy-beta-D-glucopyranose
+分子 #6: 6-(trifluoromethoxy)-1,3-benzothiazol-2-amine
+分子 #7: CHOLESTEROL HEMISUCCINATE
+分子 #8: 1-O-OCTADECYL-SN-GLYCERO-3-PHOSPHOCHOLINE
+分子 #9: 1,2-DIOLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE
+分子 #10: O-[(R)-{[(2R)-2,3-bis(octadecanoyloxy)propyl]oxy}(hydroxy)phospho...
+分子 #11: water
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
緩衝液 | pH: 7.5 |
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凍結 | 凍結剤: ETHANE |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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撮影 | フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) 検出モード: SUPER-RESOLUTION / 平均電子線量: 40.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD 最大 デフォーカス(公称値): 1.4000000000000001 µm 最小 デフォーカス(公称値): 1.2 µm |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |