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基本情報
登録情報 | データベース: PDB / ID: 7tci | ||||||
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タイトル | Structure of Xenopus KCNQ1-CaM in complex with ML277 | ||||||
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![]() | TRANSPORT PROTEIN/ACTIVATOR / Activator / ion channel / TRANSPORT PROTEIN-ACTIVATOR complex | ||||||
機能・相同性 | ![]() regulation of gastric acid secretion / membrane repolarization / outward rectifier potassium channel activity / delayed rectifier potassium channel activity / CaM pathway / Cam-PDE 1 activation / intestinal absorption / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels ...regulation of gastric acid secretion / membrane repolarization / outward rectifier potassium channel activity / delayed rectifier potassium channel activity / CaM pathway / Cam-PDE 1 activation / intestinal absorption / Sodium/Calcium exchangers / Calmodulin induced events / Reduction of cytosolic Ca++ levels / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Activation of Ca-permeable Kainate Receptor / Loss of phosphorylation of MECP2 at T308 / monoatomic ion channel complex / CREB1 phosphorylation through the activation of Adenylate Cyclase / PKA activation / negative regulation of high voltage-gated calcium channel activity / CaMK IV-mediated phosphorylation of CREB / Glycogen breakdown (glycogenolysis) / positive regulation of cyclic-nucleotide phosphodiesterase activity / organelle localization by membrane tethering / negative regulation of calcium ion export across plasma membrane / CLEC7A (Dectin-1) induces NFAT activation / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / regulation of cardiac muscle cell action potential / Activation of RAC1 downstream of NMDARs / renal absorption / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction / Negative regulation of NMDA receptor-mediated neuronal transmission / negative regulation of peptidyl-threonine phosphorylation / Synthesis of IP3 and IP4 in the cytosol / Unblocking of NMDA receptors, glutamate binding and activation / Phase 0 - rapid depolarisation / negative regulation of ryanodine-sensitive calcium-release channel activity / protein phosphatase activator activity / voltage-gated potassium channel activity / RHO GTPases activate PAKs / : / Ion transport by P-type ATPases / inner ear development / Long-term potentiation / Uptake and function of anthrax toxins / Regulation of MECP2 expression and activity / Calcineurin activates NFAT / catalytic complex / DARPP-32 events / detection of calcium ion / regulation of cardiac muscle contraction / regulation of ryanodine-sensitive calcium-release channel activity / Smooth Muscle Contraction / cellular response to interferon-beta / RHO GTPases activate IQGAPs / calcium channel inhibitor activity / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Protein methylation / eNOS activation / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / Activation of AMPK downstream of NMDARs / Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation / : / Ion homeostasis / titin binding / regulation of calcium-mediated signaling / positive regulation of protein autophosphorylation / voltage-gated potassium channel complex / sperm midpiece / calcium channel complex / phosphatidylinositol-4,5-bisphosphate binding / substantia nigra development / adenylate cyclase activator activity / Ras activation upon Ca2+ influx through NMDA receptor / regulation of heart rate / sarcomere / FCERI mediated Ca+2 mobilization / protein serine/threonine kinase activator activity / FCGR3A-mediated IL10 synthesis / VEGFR2 mediated vascular permeability / Antigen activates B Cell Receptor (BCR) leading to generation of second messengers / VEGFR2 mediated cell proliferation / regulation of cytokinesis / positive regulation of peptidyl-threonine phosphorylation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / spindle microtubule / RAF activation / positive regulation of receptor signaling pathway via JAK-STAT / cytoplasmic vesicle membrane / Transcriptional activation of mitochondrial biogenesis / positive regulation of protein serine/threonine kinase activity / Stimuli-sensing channels / cellular response to type II interferon / spindle pole / response to calcium ion / RAS processing / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / calcium-dependent protein binding 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: 3.9 Å | ||||||
![]() | Willegems, K. / Kyriakis, E. / Van Petegem, F. / Eldstrom, J. / Fedida, D. | ||||||
資金援助 | 1件
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![]() | ![]() タイトル: Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277. 著者: Katrien Willegems / Jodene Eldstrom / Efthimios Kyriakis / Fariba Ataei / Harutyun Sahakyan / Ying Dou / Sophia Russo / Filip Van Petegem / David Fedida / ![]() ![]() 要旨: The KCNQ1 ion channel plays critical physiological roles in electrical excitability and K recycling in organs including the heart, brain, and gut. Loss of function is relatively common and can cause ...The KCNQ1 ion channel plays critical physiological roles in electrical excitability and K recycling in organs including the heart, brain, and gut. Loss of function is relatively common and can cause sudden arrhythmic death, sudden infant death, epilepsy and deafness. Here, we report cryogenic electron microscopic (cryo-EM) structures of Xenopus KCNQ1 bound to Ca/Calmodulin, with and without the KCNQ1 channel activator, ML277. A single binding site for ML277 was identified, localized to a pocket lined by the S4-S5 linker, S5 and S6 helices of two separate subunits. Several pocket residues are not conserved in other KCNQ isoforms, explaining specificity. MD simulations and point mutations support this binding location for ML277 in open and closed channels and reveal that prevention of inactivation is an important component of the activator effect. Our work provides direction for therapeutic intervention targeting KCNQ1 loss of function pathologies including long QT interval syndrome and seizures. | ||||||
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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 | ![]() | 347.2 KB | 表示 | ![]() |
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PDB形式 | ![]() | 276.6 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 |
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-関連構造データ
関連構造データ | ![]() 25813MC ![]() 7tcpC 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
#1: タンパク質 | 分子量: 62663.398 Da / 分子数: 4 / 断片: UNP residues 67-610 / 由来タイプ: 組換発現 由来: (組換発現) ![]() 遺伝子: kcnq1, kvlqt1 / 細胞株 (発現宿主): HEK293 / 発現宿主: ![]() #2: タンパク質 | 分子量: 16852.545 Da / 分子数: 4 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() #3: 化合物 | ChemComp-I0S / ( #4: 化合物 | ChemComp-CA / 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: Potassium voltage-gated channel subfamily KQT member 1 in complex with calmodulin and ML277 タイプ: COMPLEX / Entity ID: #1-#2 / 由来: MULTIPLE SOURCES | |||||||||||||||||||||||||||||||||||
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分子量 | 値: 0.31756 MDa / 実験値: NO | |||||||||||||||||||||||||||||||||||
由来(天然) | 生物種: ![]() | |||||||||||||||||||||||||||||||||||
由来(組換発現) | 生物種: ![]() | |||||||||||||||||||||||||||||||||||
緩衝液 | pH: 7.2 | |||||||||||||||||||||||||||||||||||
緩衝液成分 |
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試料 | 濃度: 2 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | |||||||||||||||||||||||||||||||||||
試料支持 | グリッドの材料: COPPER / グリッドのサイズ: 400 divisions/in. / 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: 98 % / 凍結前の試料温度: 277.15 K |
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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): 4800 nm / 最小 デフォーカス(公称値): 530 nm |
試料ホルダ | 凍結剤: NITROGEN 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
撮影 | 電子線照射量: 50 e/Å2 / 検出モード: COUNTING フィルム・検出器のモデル: FEI FALCON III (4k x 4k) 撮影したグリッド数: 1 / 実像数: 4400 |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.19.2_4158: / 分類: 精密化 | ||||||||||||||||||||||||
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EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
粒子像の選択 | 選択した粒子像数: 469000 | ||||||||||||||||||||||||
対称性 | 点対称性: C4 (4回回転対称) | ||||||||||||||||||||||||
3次元再構成 | 解像度: 3.9 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 32900 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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