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基本情報
登録情報 | データベース: PDB / ID: 8i5g | |||||||||
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タイトル | Structure of human Nav1.7 in complex with PF-05089771 | |||||||||
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![]() | MEMBRANE PROTEIN / Inhibitor complex. | |||||||||
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 / circadian rhythm / response to toxic substance / Sensory perception of sweet, bitter, and umami (glutamate) taste / positive regulation of neuron projection development / 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: 2.7 Å | |||||||||
![]() | Wu, Q.R. / Yan, N. | |||||||||
資金援助 | ![]() ![]()
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![]() | ![]() タイトル: Structural mapping of Na1.7 antagonists. 著者: Qiurong Wu / Jian Huang / Xiao Fan / Kan Wang / Xueqin Jin / Gaoxingyu Huang / Jiaao Li / Xiaojing Pan / Nieng Yan / ![]() ![]() 要旨: Voltage-gated sodium (Na) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in ...Voltage-gated sodium (Na) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in structural elucidation of Na channels, the binding mode of most Na-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Na1.7 treated with drugs and lead compounds with representative chemical backbones at resolutions of 2.6-3.2 Å. A binding site beneath the intracellular gate (site BIG) accommodates carbamazepine, bupivacaine, and lacosamide. Unexpectedly, a second molecule of lacosamide plugs into the selectivity filter from the central cavity. Fenestrations are popular sites for various state-dependent drugs. We show that vinpocetine, a synthetic derivative of a vinca alkaloid, and hardwickiic acid, a natural product with antinociceptive effect, bind to the III-IV fenestration, while vixotrigine, an analgesic candidate, penetrates the IV-I fenestration of the pore domain. Our results permit building a 3D structural map for known drug-binding sites on Na channels summarized from the present and previous structures. | |||||||||
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 364.7 KB | 表示 | ![]() |
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PDB形式 | ![]() | 279.5 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 | ![]() | 2 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 2 MB | 表示 | |
XML形式データ | ![]() | 54.9 KB | 表示 | |
CIF形式データ | ![]() | 80.4 KB | 表示 | |
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 | ![]() 35194MC ![]() 8i5bC ![]() 8i5xC ![]() 8i5yC ![]() 8j4fC ![]() 8s9bC ![]() 8s9cC 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 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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リンク
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集合体
登録構造単位 | ![]()
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要素
-Sodium channel subunit beta- ... , 2種, 2分子 BC
#1: タンパク質 | 分子量: 21977.199 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
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#2: 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) ![]() ![]() |
-タンパク質 , 1種, 1分子 A
#3: 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) ![]() ![]() |
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-糖 , 2種, 8分子 ![](data/chem/img/NAG.gif)
#4: 多糖 | #5: 糖 | ChemComp-NAG / |
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-非ポリマー , 7種, 23分子 ![](data/chem/img/Y01.gif)
![](data/chem/img/9Z9.gif)
![](data/chem/img/T70.gif)
![](data/chem/img/NA.gif)
![](data/chem/img/LPE.gif)
![](data/chem/img/PCW.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/9Z9.gif)
![](data/chem/img/T70.gif)
![](data/chem/img/NA.gif)
![](data/chem/img/LPE.gif)
![](data/chem/img/PCW.gif)
![](data/chem/img/HOH.gif)
#6: 化合物 | #7: 化合物 | ChemComp-9Z9 / ( | #8: 化合物 | ChemComp-T70 / | #9: 化合物 | ChemComp-NA / | #10: 化合物 | ChemComp-LPE / #11: 化合物 | ChemComp-PCW / #12: 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 |
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試料調製
構成要素 | 名称: human Nav1.7 in complex with bupivacaine / タイプ: COMPLEX / Entity ID: #1-#3 / 由来: RECOMBINANT |
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分子量 | 値: 0.25 MDa / 実験値: YES |
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 |
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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): 1800 nm / 最小 デフォーカス(公称値): 1500 nm |
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 | 名称: PHENIX / バージョン: 1.20.1_4487: / 分類: 精密化 | ||||||||||||||||||||||||
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3次元再構成 | 解像度: 2.7 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 297950 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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