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基本情報
登録情報 | データベース: PDB / ID: 8dgs | ||||||||||||
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タイトル | Cryo-EM structure of a RAS/RAF complex (state 1) | ||||||||||||
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![]() | TRANSFERASE / kinase complex | ||||||||||||
機能・相同性 | ![]() epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / CD4-positive, alpha-beta T cell differentiation / placenta blood vessel development / trehalose metabolism in response to stress / regulation of axon regeneration / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / mitogen-activated protein kinase kinase / negative regulation of synaptic vesicle exocytosis / labyrinthine layer development ...epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / CD4-positive, alpha-beta T cell differentiation / placenta blood vessel development / trehalose metabolism in response to stress / regulation of axon regeneration / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / mitogen-activated protein kinase kinase / negative regulation of synaptic vesicle exocytosis / labyrinthine layer development / MAP-kinase scaffold activity / type B pancreatic cell proliferation / Signalling to p38 via RIT and RIN / cerebellar cortex formation / head morphogenesis / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / endothelial cell apoptotic process / Signaling by MAP2K mutants / negative regulation of fibroblast migration / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / regulation of Golgi inheritance / mitogen-activated protein kinase kinase binding / trachea formation / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / positive regulation of axonogenesis / regulation of stress-activated MAPK cascade / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / stress fiber assembly / positive regulation of axon regeneration / protein kinase activator activity / endodermal cell differentiation / face development / MAPK3 (ERK1) activation / synaptic vesicle exocytosis / somatic stem cell population maintenance / Bergmann glial cell differentiation / MAP kinase kinase activity / thyroid gland development / Uptake and function of anthrax toxins / MAP kinase kinase kinase activity / Schwann cell development / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / keratinocyte differentiation / positive regulation of stress fiber assembly / response to cAMP / cellular response to calcium ion / ERK1 and ERK2 cascade / myelination / protein serine/threonine/tyrosine kinase activity / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / substrate adhesion-dependent cell spreading / insulin-like growth factor receptor signaling pathway / small monomeric GTPase / cellular response to nerve growth factor stimulus / thymus development / Signal transduction by L1 / cell motility / long-term synaptic potentiation / animal organ morphogenesis / RAF activation / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / visual learning / MAP2K and MAPK activation / positive regulation of protein serine/threonine kinase activity / neuron differentiation / epidermal growth factor receptor signaling pathway / response to peptide hormone / Negative regulation of MAPK pathway / 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 / GDP binding / chemotaxis / MAPK cascade / cellular senescence / Signaling by BRAF and RAF1 fusions / cellular response to xenobiotic stimulus / late endosome / presynapse / positive regulation of peptidyl-serine phosphorylation / heart development / T cell receptor signaling pathway / regulation of cell population proliferation / cell body / T cell differentiation in thymus / scaffold protein binding / protein tyrosine kinase activity / negative regulation of neuron apoptotic process / Ras protein signal transduction 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: 4.3 Å | ||||||||||||
![]() | Eck, M.J. / Jeon, H. / Park, E. / Rawson, S. | ||||||||||||
資金援助 | ![]()
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![]() | ![]() タイトル: Cryo-EM structure of a RAS/RAF recruitment complex. 著者: Eunyoung Park / Shaun Rawson / Anna Schmoker / Byeong-Won Kim / Sehee Oh / Kangkang Song / Hyesung Jeon / Michael J Eck / ![]() ![]() 要旨: RAF-family kinases are activated by recruitment to the plasma membrane by GTP-bound RAS, whereupon they initiate signaling through the MAP kinase cascade. Prior structural studies of KRAS with RAF ...RAF-family kinases are activated by recruitment to the plasma membrane by GTP-bound RAS, whereupon they initiate signaling through the MAP kinase cascade. Prior structural studies of KRAS with RAF have focused on the isolated RAS-binding and cysteine-rich domains of RAF (RBD and CRD, respectively), which interact directly with RAS. Here we describe cryo-EM structures of a KRAS bound to intact BRAF in an autoinhibited state with MEK1 and a 14-3-3 dimer. Analysis of this KRAS/BRAF/MEK1/14-3-3 complex reveals KRAS bound to the RAS-binding domain of BRAF, captured in two orientations. Core autoinhibitory interactions in the complex are unperturbed by binding of KRAS and in vitro activation studies confirm that KRAS binding is insufficient to activate BRAF, absent membrane recruitment. These structures illustrate the separability of binding and activation of BRAF by RAS and suggest stabilization of this pre-activation intermediate as an alternative therapeutic strategy to blocking binding of KRAS. | ||||||||||||
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構造の表示
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 | ![]() | 269.1 KB | 表示 | ![]() |
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PDB形式 | ![]() | 211.4 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 | ![]() | 1.5 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.5 MB | 表示 | |
XML形式データ | ![]() | 56.3 KB | 表示 | |
CIF形式データ | ![]() | 81.5 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
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リンク
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集合体
登録構造単位 | ![]()
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1 |
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要素
-タンパク質 , 4種, 5分子 ABCDE
#1: タンパク質 | 分子量: 89402.789 Da / 分子数: 1 / 由来タイプ: 組換発現 / 詳細: ATPgS / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: P15056, non-specific serine/threonine protein kinase | ||
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#2: タンパク質 | 分子量: 45835.414 Da / 分子数: 1 / 由来タイプ: 組換発現 / 詳細: GDC-0623, ATPgS / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: Q02750, mitogen-activated protein kinase kinase | ||
#3: タンパク質 | 分子量: 28108.514 Da / 分子数: 2 / 由来タイプ: 組換発現 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: V9P4T4 #4: タンパク質 | | 分子量: 21868.625 Da / 分子数: 1 / 由来タイプ: 組換発現 / 詳細: GMPPNP / 由来: (組換発現) ![]() ![]() ![]() |
-非ポリマー , 5種, 8分子 ![](data/chem/img/AGS.gif)
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![](data/chem/img/GNP.gif)
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#5: 化合物 | #6: 化合物 | #7: 化合物 | #8: 化合物 | ChemComp-LCJ / | #9: 化合物 | ChemComp-GNP / | |
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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: Kinase Complex state-1 / タイプ: COMPLEX / Entity ID: #1-#3 / 由来: MULTIPLE SOURCES | ||||||||||||
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分子量 | 値: 0.225 MDa / 実験値: YES | ||||||||||||
由来(天然) |
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由来(組換発現) |
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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 | ||||||||||||
試料支持 | グリッドの材料: COPPER | ||||||||||||
急速凍結 | 装置: LEICA EM GP / 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: OTHER / 最大 デフォーカス(公称値): 2800 nm / 最小 デフォーカス(公称値): 1800 nm |
撮影 | 電子線照射量: 45.6 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
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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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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3次元再構成 | 解像度: 4.3 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 69377 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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