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データを開く
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基本情報
登録情報 | データベース: PDB / ID: 7svd | |||||||||
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タイトル | The complex of phosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) with ATP/Mg and Lumacaftor (VX-809) | |||||||||
![]() | (Cystic fibrosis transmembrane conductance ...) x 2 | |||||||||
![]() | ATP-BINDING PROTEIN / ABC transporter / ion channel / folding correction / MEMBRANE PROTEIN | |||||||||
機能・相同性 | ![]() positive regulation of voltage-gated chloride channel activity / positive regulation of cyclic nucleotide-gated ion channel activity / Sec61 translocon complex binding / channel-conductance-controlling ATPase / intracellularly ATP-gated chloride channel activity / positive regulation of enamel mineralization / transepithelial water transport / RHO GTPases regulate CFTR trafficking / intracellular pH elevation / amelogenesis ...positive regulation of voltage-gated chloride channel activity / positive regulation of cyclic nucleotide-gated ion channel activity / Sec61 translocon complex binding / channel-conductance-controlling ATPase / intracellularly ATP-gated chloride channel activity / positive regulation of enamel mineralization / transepithelial water transport / RHO GTPases regulate CFTR trafficking / intracellular pH elevation / amelogenesis / chloride channel inhibitor activity / ATPase-coupled inorganic anion transmembrane transporter activity / Golgi-associated vesicle membrane / multicellular organismal-level water homeostasis / cholesterol transport / membrane hyperpolarization / bicarbonate transport / bicarbonate transmembrane transporter activity / vesicle docking involved in exocytosis / chloride channel regulator activity / chloride transmembrane transporter activity / sperm capacitation / chloride channel activity / cholesterol biosynthetic process / RHOQ GTPase cycle / positive regulation of exocytosis / positive regulation of insulin secretion involved in cellular response to glucose stimulus / chloride channel complex / ATPase-coupled transmembrane transporter activity / ABC-type transporter activity / cellular response to cAMP / cellular response to forskolin / chloride transmembrane transport / response to endoplasmic reticulum stress / isomerase activity / establishment of localization in cell / PDZ domain binding / Defective CFTR causes cystic fibrosis / Late endosomal microautophagy / clathrin-coated endocytic vesicle membrane / ABC-family proteins mediated transport / recycling endosome / transmembrane transport / Aggrephagy / Chaperone Mediated Autophagy / recycling endosome membrane / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / protein-folding chaperone binding / early endosome membrane / early endosome / endosome membrane / Ub-specific processing proteases / apical plasma membrane / lysosomal membrane / endoplasmic reticulum membrane / enzyme binding / cell surface / ATP hydrolysis activity / protein-containing complex / ATP binding / membrane / nucleus / plasma membrane / cytosol / cytoplasm 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 | |||||||||
![]() | Fiedorczuk, K. / Chen, J. | |||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Mechanism of CFTR correction by type I folding correctors. 著者: Karol Fiedorczuk / Jue Chen / ![]() 要旨: Small molecule chaperones have been exploited as therapeutics for the hundreds of diseases caused by protein misfolding. The most successful examples are the CFTR correctors, which transformed cystic ...Small molecule chaperones have been exploited as therapeutics for the hundreds of diseases caused by protein misfolding. The most successful examples are the CFTR correctors, which transformed cystic fibrosis therapy. These molecules revert folding defects of the ΔF508 mutant and are widely used to treat patients. To investigate the molecular mechanism of their action, we determined cryo-electron microscopy structures of CFTR in complex with the FDA-approved correctors lumacaftor or tezacaftor. Both drugs insert into a hydrophobic pocket in the first transmembrane domain (TMD1), linking together four helices that are thermodynamically unstable. Mutating residues at the binding site rendered ΔF508-CFTR insensitive to lumacaftor and tezacaftor, underscoring the functional significance of the structural discovery. These results support a mechanism in which the correctors stabilize TMD1 at an early stage of biogenesis, prevent its premature degradation, and thereby allosterically rescuing many disease-causing mutations. | |||||||||
履歴 |
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構造の表示
ムービー |
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構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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ダウンロード
PDBx/mmCIF形式 | ![]() | 232.4 KB | 表示 | ![]() |
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PDB形式 | ![]() | 178.6 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 | ![]() 25447MC ![]() 7sv7C ![]() 7svrC C: 同じ文献を引用 ( M: このデータのモデリングに利用したマップデータ |
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類似構造データ | |
電子顕微鏡画像生データ | ![]() Data size: 5.8 TB Data #1: Unaligned multi-frame micrographs of phosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) with ATP/Mg and Lumacaftor (VX-809) [micrographs - multiframe]) |
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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
-Cystic fibrosis transmembrane conductance ... , 2種, 2分子 AB
#1: タンパク質 | 分子量: 168334.469 Da / 分子数: 1 / 変異: E1371Q / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() 参照: UniProt: P13569, channel-conductance-controlling ATPase |
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#2: タンパク質・ペプチド | 分子量: 1464.797 Da / 分子数: 1 / Fragment: unstructured R-domain of CFTR / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
-非ポリマー , 8種, 14分子 ![](data/chem/img/MG.gif)
![](data/chem/img/ATP.gif)
![](data/chem/img/D12.gif)
![](data/chem/img/D10.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/VX8.gif)
![](data/chem/img/UNX.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/ATP.gif)
![](data/chem/img/D12.gif)
![](data/chem/img/D10.gif)
![](data/chem/img/CLR.gif)
![](data/chem/img/VX8.gif)
![](data/chem/img/UNX.gif)
![](data/chem/img/HOH.gif)
#3: 化合物 | #4: 化合物 | #5: 化合物 | ChemComp-D12 / | #6: 化合物 | #7: 化合物 | #8: 化合物 | ChemComp-VX8 / | #9: 化合物 | ChemComp-UNX / | #10: 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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配列の詳細 | Chain B is R-domain of the CFTR polypeptide chain and is mostly unstructured. It is not possible to ...Chain B is R-domain of the CFTR polypeptide chain and is mostly unstructured. It is not possible to assign it a sequence or correct registry. |
-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: The complex of phosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) with ATP/Mg and Lumacaftor (VX-809) タイプ: COMPLEX / Entity ID: #1-#2 / 由来: RECOMBINANT |
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由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() |
緩衝液 | pH: 7.4 |
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): 2000 nm / 最小 デフォーカス(公称値): 1000 nm |
撮影 | 電子線照射量: 98 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: 1.18.2_3874: / 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: 52920 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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