+
データを開く
-
基本情報
登録情報 | データベース: PDB / ID: 8thg | ||||||
---|---|---|---|---|---|---|---|
タイトル | Cryo-EM structure of Nav1.7 with RLZ | ||||||
![]() |
| ||||||
![]() | MEMBRANE PROTEIN / Cryo-EM / sodium channel / VGSC / Nav1.7 | ||||||
機能・相同性 | ![]() 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 Purkinje myocyte action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / membrane depolarization during Purkinje myocyte cell action potential / regulation of atrial cardiac muscle cell membrane depolarization ...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 Purkinje myocyte action potential / voltage-gated sodium channel activity involved in cardiac muscle cell action potential / regulation of sodium ion transmembrane transporter activity / voltage-gated potassium channel activity involved in ventricular cardiac muscle cell action potential repolarization / membrane depolarization during Purkinje myocyte cell action potential / regulation of atrial cardiac muscle cell membrane depolarization / cardiac conduction / membrane depolarization during cardiac muscle cell action potential / positive regulation of sodium ion transport / node of Ranvier / cardiac muscle cell action potential involved in contraction / regulation of ventricular cardiac muscle cell membrane repolarization / voltage-gated sodium channel complex / sodium channel inhibitor activity / locomotion / neuronal action potential propagation / Interaction between L1 and Ankyrins / voltage-gated sodium channel activity / sodium ion transport / Phase 0 - rapid depolarisation / behavioral response to pain / regulation of heart rate by cardiac conduction / detection of temperature stimulus involved in sensory perception of pain / membrane depolarization / intercalated disc / sodium ion transmembrane transport / sodium channel regulator activity / cardiac muscle contraction / sensory perception of pain / T-tubule / post-embryonic development / axon guidance / response to toxic substance / Sensory perception of sweet, bitter, and umami (glutamate) taste / positive regulation of neuron projection development / 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 | ![]() | ||||||
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: 2.9 Å | ||||||
![]() | Fan, X. / Huang, J. / Yan, N. | ||||||
資金援助 | ![]()
| ||||||
![]() | ![]() 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 |
|
-
構造の表示
構造ビューア | 分子: ![]() ![]() |
---|
-
ダウンロードとリンク
-
ダウンロード
PDBx/mmCIF形式 | ![]() | 357.8 KB | 表示 | ![]() |
---|---|---|---|---|
PDB形式 | ![]() | 274.2 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
---|
-関連構造データ
関連構造データ | ![]() 41261MC ![]() 8thhC 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 ( |
---|---|
類似構造データ | 類似検索 - 機能・相同性 ![]() |
-
リンク
-
集合体
登録構造単位 | ![]()
|
---|---|
1 |
|
-
要素
-タンパク質 , 1種, 1分子 A
#1: タンパク質 | 分子量: 226620.047 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
---|
-Sodium channel subunit beta- ... , 2種, 2分子 BC
#2: タンパク質 | 分子量: 24732.115 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
---|---|
#3: タンパク質 | 分子量: 24355.859 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
-糖 , 2種, 8分子 ![](data/chem/img/NAG.gif)
#4: 多糖 | #5: 糖 | ChemComp-NAG / |
---|
-非ポリマー , 6種, 16分子 ![](data/chem/img/657.gif)
![](data/chem/img/Y01.gif)
![](data/chem/img/LPE.gif)
![](data/chem/img/PCW.gif)
![](data/chem/img/P5S.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/Y01.gif)
![](data/chem/img/LPE.gif)
![](data/chem/img/PCW.gif)
![](data/chem/img/P5S.gif)
![](data/chem/img/HOH.gif)
#6: 化合物 | ChemComp-657 / | ||||||||
---|---|---|---|---|---|---|---|---|---|
#7: 化合物 | #8: 化合物 | ChemComp-LPE / #9: 化合物 | ChemComp-PCW / | #10: 化合物 | ChemComp-P5S / | #11: 水 | ChemComp-HOH / | |
-詳細
研究の焦点であるリガンドがあるか | Y |
---|
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
---|---|
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: Human voltage-gated sodium channel Nav1.7 with beta subunits タイプ: COMPLEX / Entity ID: #1-#3 / 由来: RECOMBINANT |
---|---|
分子量 | 実験値: NO |
由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() |
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 |
---|---|
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): 1400 nm / 最小 デフォーカス(公称値): 1200 nm |
撮影 | 電子線照射量: 40 e/Å2 / 検出モード: SUPER-RESOLUTION フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) |
-
解析
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
3次元再構成 | 解像度: 2.9 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 125461 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
|