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基本情報
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タイトル | Structure of PKA phosphorylated human RyR2-R2474S in the open state in the presence of Calmodulin | |||||||||
![]() | Composite map of the Structure of PKA phosphorylated human RyR2-R2474S in the open state in the presence of Calmodulin. | |||||||||
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機能・相同性 | ![]() junctional sarcoplasmic reticulum membrane / suramin binding / establishment of protein localization to endoplasmic reticulum / type B pancreatic cell apoptotic process / Purkinje myocyte to ventricular cardiac muscle cell signaling / regulation of SA node cell action potential / regulation of atrial cardiac muscle cell action potential / left ventricular cardiac muscle tissue morphogenesis / regulation of AV node cell action potential / positive regulation of ATPase-coupled calcium transmembrane transporter activity ...junctional sarcoplasmic reticulum membrane / suramin binding / establishment of protein localization to endoplasmic reticulum / type B pancreatic cell apoptotic process / Purkinje myocyte to ventricular cardiac muscle cell signaling / regulation of SA node cell action potential / regulation of atrial cardiac muscle cell action potential / left ventricular cardiac muscle tissue morphogenesis / regulation of AV node cell action potential / positive regulation of ATPase-coupled calcium transmembrane transporter activity / calcium-induced calcium release activity / sarcoplasmic reticulum calcium ion transport / ventricular cardiac muscle cell action potential / regulation of ventricular cardiac muscle cell action potential / positive regulation of sequestering of calcium ion / cyclic nucleotide binding / embryonic heart tube morphogenesis / cardiac muscle hypertrophy / negative regulation of insulin secretion involved in cellular response to glucose stimulus / negative regulation of release of sequestered calcium ion into cytosol / ryanodine-sensitive calcium-release channel activity / regulation of cardiac muscle contraction by calcium ion signaling / neuronal action potential propagation / insulin secretion involved in cellular response to glucose stimulus / response to muscle activity / release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / CaM pathway / Cam-PDE 1 activation / calcium ion transport into cytosol / Sodium/Calcium exchangers / response to caffeine / cell communication by electrical coupling involved in cardiac conduction / Calmodulin induced events / response to redox state / protein maturation by protein folding / Reduction of cytosolic Ca++ levels / CREB1 phosphorylation through the activation of CaMKII/CaMKK/CaMKIV cascasde / Activation of Ca-permeable Kainate Receptor / 'de novo' protein folding / Loss of phosphorylation of MECP2 at T308 / 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 / positive regulation of cyclic-nucleotide phosphodiesterase activity / Glycogen breakdown (glycogenolysis) / negative regulation of heart rate / organelle localization by membrane tethering / negative regulation of calcium ion export across plasma membrane / CLEC7A (Dectin-1) induces NFAT activation / regulation of cardiac muscle cell action potential / mitochondrion-endoplasmic reticulum membrane tethering / autophagosome membrane docking / negative regulation of phosphoprotein phosphatase activity / positive regulation of heart rate / Activation of RAC1 downstream of NMDARs / FK506 binding / positive regulation of ryanodine-sensitive calcium-release channel activity / regulation of cell communication by electrical coupling involved in cardiac conduction / positive regulation of axon regeneration / Negative regulation of NMDA receptor-mediated neuronal transmission / negative regulation of peptidyl-threonine phosphorylation / cellular response to caffeine / Synthesis of IP3 and IP4 in the cytosol / Unblocking of NMDA receptors, glutamate binding and activation / Phase 0 - rapid depolarisation / protein kinase A regulatory subunit binding / protein phosphatase activator activity / intracellularly gated calcium channel activity / protein kinase A catalytic subunit binding / RHO GTPases activate PAKs / positive regulation of the force of heart contraction / positive regulation of phosphoprotein phosphatase activity / Ion transport by P-type ATPases / 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 / smooth muscle contraction / regulation of cardiac muscle contraction / smooth endoplasmic reticulum / negative regulation of ryanodine-sensitive calcium-release channel activity / Smooth Muscle Contraction / response to vitamin E / calcium channel inhibitor activity / RHO GTPases activate IQGAPs / cellular response to interferon-beta / regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion / Protein methylation / protein peptidyl-prolyl isomerization / eNOS activation / T cell proliferation / Activation of AMPK downstream of NMDARs / striated muscle contraction / regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum / cardiac muscle contraction 類似検索 - 分子機能 | |||||||||
生物種 | ![]() | |||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 2.93 Å | |||||||||
![]() | Miotto MC / Marks AR | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Structural analyses of human ryanodine receptor type 2 channels reveal the mechanisms for sudden cardiac death and treatment. 著者: Marco C Miotto / Gunnar Weninger / Haikel Dridi / Qi Yuan / Yang Liu / Anetta Wronska / Zephan Melville / Leah Sittenfeld / Steven Reiken / Andrew R Marks / ![]() 要旨: Ryanodine receptor type 2 (RyR2) mutations have been linked to an inherited form of exercise-induced sudden cardiac death called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT ...Ryanodine receptor type 2 (RyR2) mutations have been linked to an inherited form of exercise-induced sudden cardiac death called catecholaminergic polymorphic ventricular tachycardia (CPVT). CPVT results from stress-induced sarcoplasmic reticular Ca leak via the mutant RyR2 channels during diastole. We present atomic models of human wild-type (WT) RyR2 and the CPVT mutant RyR2-R2474S determined by cryo-electron microscopy with overall resolutions in the range of 2.6 to 3.6 Å, and reaching local resolutions of 2.25 Å, unprecedented for RyR2 channels. Under nonactivating conditions, the RyR2-R2474S channel is in a "primed" state between the closed and open states of WT RyR2, rendering it more sensitive to activation that results in stress-induced Ca leak. The Rycal drug ARM210 binds to RyR2-R2474S, reverting the primed state toward the closed state. Together, these studies provide a mechanism for CPVT and for the therapeutic actions of ARM210. | |||||||||
履歴 |
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-検証レポート
文書・要旨 | ![]() | 420.5 KB | 表示 | ![]() |
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文書・詳細版 | ![]() | 420.1 KB | 表示 | |
XML形式データ | ![]() | 8 KB | 表示 | |
CIF形式データ | ![]() | 9.2 KB | 表示 | |
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-関連構造データ
関連構造データ | ![]() 7ua4MC ![]() 7u9qC ![]() 7u9rC ![]() 7u9tC ![]() 7u9xC ![]() 7u9zC ![]() 7ua1C ![]() 7ua3C ![]() 7ua5C ![]() 7ua9C 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 ( |
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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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「今月の分子」の関連する項目 |
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マップ
ファイル | ![]() | ||||||||||||||||||||
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注釈 | Composite map of the Structure of PKA phosphorylated human RyR2-R2474S in the open state in the presence of Calmodulin. | ||||||||||||||||||||
ボクセルのサイズ | X=Y=Z: 0.832 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
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試料の構成要素
+全体 : Complex of RyR2-R2474S, Calstabin-2, and Calmodulin
+超分子 #1: Complex of RyR2-R2474S, Calstabin-2, and Calmodulin
+超分子 #2: Ryanodine receptor 2
+超分子 #3: Peptidyl-prolyl cis-trans isomerase FKBP1B (E.C.5.2.1.8), Calmodulin-1
+分子 #1: Ryanodine receptor 2
+分子 #2: Peptidyl-prolyl cis-trans isomerase FKBP1B
+分子 #3: Calmodulin-1
+分子 #4: ZINC ION
+分子 #5: ADENOSINE-5'-TRIPHOSPHATE
+分子 #6: CALCIUM ION
+分子 #7: XANTHINE
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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![]() | 単粒子再構成法 |
試料の集合状態 | particle |
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試料調製
濃度 | 2.2 mg/mL | |||||||||||||||||||||||||||||||||
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緩衝液 | pH: 7.4 構成要素:
詳細: Xanthine was made fresh to avoid aggregation. Xanthine stock solution was 10 mM in NaOH 0.5 N. | |||||||||||||||||||||||||||||||||
グリッド | モデル: UltrAuFoil R0.6/1 / 材質: GOLD / 前処理 - タイプ: GLOW DISCHARGE | |||||||||||||||||||||||||||||||||
凍結 | 凍結剤: ETHANE / 装置: FEI VITROBOT MARK IV | |||||||||||||||||||||||||||||||||
詳細 | 40 uM of Calmodulin was added to the final sample. |
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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: GATAN K3 BIOQUANTUM (6k x 4k) デジタル化 - サイズ - 横: 5760 pixel / デジタル化 - サイズ - 縦: 4092 pixel / 平均電子線量: 58.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: ![]() |
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): 1.2 µm / 最小 デフォーカス(公称値): 0.4 µm |
実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |