+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 6nyb | |||||||||
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タイトル | Structure of a MAPK pathway complex | |||||||||
要素 |
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キーワード | TRANSFERASE | |||||||||
機能・相同性 | 機能・相同性情報 epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / CD4-positive, alpha-beta T cell differentiation / placenta blood vessel development / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / regulation of axon regeneration / mitogen-activated protein kinase kinase / myeloid progenitor cell differentiation / 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 / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / regulation of axon regeneration / mitogen-activated protein kinase kinase / myeloid progenitor cell differentiation / 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 / 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 D-glucose transmembrane transport / establishment of protein localization to membrane / regulation of Golgi inheritance / spindle pole body / mitogen-activated protein kinase kinase binding / regulation of T cell differentiation / trachea formation / 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 / stress fiber assembly / protein kinase activator activity / ERBB2-ERBB3 signaling pathway / positive regulation of axon regeneration / MAPK3 (ERK1) activation / endodermal cell differentiation / face development / somatic stem cell population maintenance / MAP kinase kinase activity / synaptic vesicle exocytosis / Bergmann glial cell differentiation / Uptake and function of anthrax toxins / thyroid gland development / MAP kinase kinase kinase activity / negative regulation of endothelial cell apoptotic process / Schwann cell development / positive regulation of substrate adhesion-dependent cell spreading / keratinocyte differentiation / positive regulation of stress fiber assembly / response to cAMP / protein serine/threonine/tyrosine kinase activity / myelination / cellular response to calcium ion / ERK1 and ERK2 cascade / substrate adhesion-dependent cell spreading / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / insulin-like growth factor receptor signaling pathway / thymus development / cellular response to nerve growth factor stimulus / Signal transduction by L1 / cell motility / long-term synaptic potentiation / animal organ morphogenesis / RAF activation / Signaling by high-kinase activity BRAF mutants / Spry regulation of FGF signaling / MAP2K and MAPK activation / visual learning / epidermal growth factor receptor signaling pathway / positive regulation of protein serine/threonine kinase activity / neuron differentiation / 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 / chemotaxis / Signaling by BRAF and RAF1 fusions / cellular senescence / MAPK cascade / late endosome / cellular response to xenobiotic stimulus / positive regulation of peptidyl-serine phosphorylation / heart development / presynapse / regulation of cell population proliferation / T cell receptor signaling pathway / T cell differentiation in thymus / cell body / scaffold protein binding / protein tyrosine kinase activity / negative regulation of neuron apoptotic process / positive regulation of ERK1 and ERK2 cascade / early endosome / non-specific serine/threonine protein kinase 類似検索 - 分子機能 | |||||||||
生物種 | Homo sapiens (ヒト) Spodoptera exigua (シロイチモジヨトウ) | |||||||||
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: 4.1 Å | |||||||||
データ登録者 | Park, E. / Rawson, S. / Li, K. / Jeon, H. / Eck, M.J. | |||||||||
資金援助 | 米国, 2件
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引用 | ジャーナル: Nature / 年: 2019 タイトル: Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes. 著者: Eunyoung Park / Shaun Rawson / Kunhua Li / Byeong-Won Kim / Scott B Ficarro / Gonzalo Gonzalez-Del Pino / Humayun Sharif / Jarrod A Marto / Hyesung Jeon / Michael J Eck / 要旨: RAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly ...RAF family kinases are RAS-activated switches that initiate signalling through the MAP kinase cascade to control cellular proliferation, differentiation and survival. RAF activity is tightly regulated and inappropriate activation is a frequent cause of cancer; however, the structural basis for RAF regulation is poorly understood at present. Here we use cryo-electron microscopy to determine autoinhibited and active-state structures of full-length BRAF in complexes with MEK1 and a 14-3-3 dimer. The reconstruction reveals an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer, which binds the phosphorylated S365 and S729 sites that flank the BRAF kinase domain. The BRAF cysteine-rich domain occupies a central position that stabilizes this assembly, but the adjacent RAS-binding domain is poorly ordered and peripheral. The 14-3-3 cradle maintains autoinhibition by sequestering the membrane-binding cysteine-rich domain and blocking dimerization of the BRAF kinase domain. In the active state, these inhibitory interactions are released and a single 14-3-3 dimer rearranges to bridge the C-terminal pS729 binding sites of two BRAFs, which drives the formation of an active, back-to-back BRAF dimer. Our structural snapshots provide a foundation for understanding normal RAF regulation and its mutational disruption in cancer and developmental syndromes. | |||||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | 分子: MolmilJmol/JSmol |
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 6nyb.cif.gz | 218 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb6nyb.ent.gz | 170.4 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 6nyb.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
その他 | その他のダウンロード |
-検証レポート
文書・要旨 | 6nyb_validation.pdf.gz | 983.6 KB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 6nyb_full_validation.pdf.gz | 992.9 KB | 表示 | |
XML形式データ | 6nyb_validation.xml.gz | 39.6 KB | 表示 | |
CIF形式データ | 6nyb_validation.cif.gz | 58.5 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/ny/6nyb ftp://data.pdbj.org/pub/pdb/validation_reports/ny/6nyb | HTTPS FTP |
-関連構造データ
-リンク
-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 , 3種, 4分子 ABCD
#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 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: BRAF, BRAF1, RAFB1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P15056, non-specific serine/threonine protein kinase |
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#2: タンパク質 | 分子量: 45934.543 Da / 分子数: 1 / Mutation: S218A, S222A / 由来タイプ: 組換発現 / 詳細: GDC-0623 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: MAP2K1, MEK1, PRKMK1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 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: 天然 由来: (天然) Spodoptera exigua (シロイチモジヨトウ) 参照: UniProt: V9P4T4 |
-非ポリマー , 5種, 6分子
#4: 化合物 | ChemComp-AGS / | ||||||
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#5: 化合物 | #6: 化合物 | ChemComp-ADP / | #7: 化合物 | ChemComp-MG / | #8: 化合物 | ChemComp-LCJ / | |
-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 |
-試料調製
構成要素 | 名称: Ternary complex of BRAF/MEK1/14-3-3 with MEK inhibitor タイプ: COMPLEX 詳細: 14-3-3 is heterodimer of Insect epsilon and zeta. model was generated by Insect zeta sequence as a homo-dimer. Entity ID: #1-#3 / 由来: MULTIPLE SOURCES |
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分子量 | 値: 0.19 MDa / 実験値: YES |
由来(天然) | 生物種: Homo sapiens (ヒト) |
緩衝液 | pH: 7.4 |
試料 | 濃度: 0.05 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
試料支持 | 詳細: unspecified |
急速凍結 | 凍結剤: ETHANE |
-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: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: OTHER |
電子レンズ | モード: OTHER / Cs: 2.7 mm / C2レンズ絞り径: 70 µm |
撮影 | 電子線照射量: 50 e/Å2 フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
-解析
ソフトウェア | 名称: PHENIX / バージョン: 1.15.2_3472: / 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: 4.1 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 165298 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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