登録情報 データベース : EMDB / ID : EMD-27429 ダウンロードとリンクタイトル Cryo-EM structure of a RAS/RAF complex (state 2) マップデータ 詳細 試料複合体 : Kinase Complex state-1タンパク質・ペプチド : Serine/threonine-protein kinase B-rafタンパク質・ペプチド : Dual specificity mitogen-activated protein kinase kinase 1タンパク質・ペプチド : 14-3-3 protein zetaタンパク質・ペプチド : GTPase KRas isoform X2リガンド : PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTERリガンド : ZINC IONリガンド : MAGNESIUM IONリガンド : 5-[(2-fluoro-4-iodophenyl)amino]-N-(2-hydroxyethoxy)imidazo[1,5-a]pyridine-6-carboxamideリガンド : PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER 残り3件を表示 表示を減らす 詳細 キーワード kinase complex / TRANSFERASE機能・相同性 機能・相同性情報分子機能 ドメイン・相同性 構成要素
epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / CD4-positive, alpha-beta T cell differentiation / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / labyrinthine layer development / MAP-kinase scaffold activity ... epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / CD4-positive, alpha-beta T cell differentiation / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / 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 / spindle pole body / MAP kinase kinase kinase activity / 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 / regulation of stress-activated MAPK cascade / positive regulation of axonogenesis / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / stress fiber assembly / protein kinase activator activity / positive regulation of axon regeneration / endodermal cell differentiation / MAPK3 (ERK1) activation / face development / synaptic vesicle exocytosis / somatic stem cell population maintenance / MAP kinase kinase activity / Bergmann glial cell differentiation / thyroid gland development / Uptake and function of anthrax toxins / negative regulation of endothelial cell apoptotic process / Schwann cell development / positive regulation of substrate adhesion-dependent cell spreading / keratinocyte differentiation / Signal transduction by L1 / positive regulation of stress fiber assembly / response to cAMP / cellular response to calcium ion / ERK1 and ERK2 cascade / protein serine/threonine/tyrosine kinase activity / myelination / substrate adhesion-dependent cell spreading / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / insulin-like growth factor receptor signaling pathway / small monomeric GTPase / cellular response to nerve growth factor stimulus / thymus development / epidermal growth factor receptor signaling pathway / cell motility / long-term synaptic potentiation / animal organ morphogenesis / RAF activation / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / positive regulation of protein serine/threonine kinase activity / cellular senescence / neuron differentiation / response to peptide hormone / cellular response to xenobiotic stimulus / 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 / positive regulation of peptidyl-serine phosphorylation / MAPK cascade / Signaling by BRAF and RAF1 fusions / late endosome / presynapse / heart development / T cell receptor signaling pathway / regulation of cell population proliferation / protein tyrosine kinase activity / cell body / T cell differentiation in thymus / scaffold protein binding / Ras protein signal transduction / negative regulation of neuron apoptotic process 類似検索 - 分子機能 : / Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / small GTPase Rab1 family profile. / : / small GTPase Rho family profile. / Phorbol esters/diacylglycerol binding domain (C1 domain) ... : / Raf-like Ras-binding domain / Raf-like Ras-binding / Ras-binding domain (RBD) profile. / Raf-like Ras-binding domain / Diacylglycerol/phorbol-ester binding / small GTPase Rab1 family profile. / : / small GTPase Rho family profile. / Phorbol esters/diacylglycerol binding domain (C1 domain) / Zinc finger phorbol-ester/DAG-type signature. / Zinc finger phorbol-ester/DAG-type profile. / Protein kinase C conserved region 1 (C1) domains (Cysteine-rich domains) / Protein kinase C-like, phorbol ester/diacylglycerol-binding domain / C1-like domain superfamily / 14-3-3 proteins signature 2. / 14-3-3 protein, conserved site / 14-3-3 proteins signature 1. / 14-3-3 protein / 14-3-3 homologues / 14-3-3 domain / 14-3-3 domain superfamily / 14-3-3 protein / Small GTPase, Ras-type / small GTPase Ras family profile. / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Small GTP-binding protein domain / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Ubiquitin-like domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Serine/Threonine protein kinases, catalytic domain / Protein kinase domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase 類似検索 - ドメイン・相同性 GTPase KRas / Serine/threonine-protein kinase B-raf / Dual specificity mitogen-activated protein kinase kinase 1 / 14-3-3 protein zeta 類似検索 - 構成要素生物種 Homo sapiens (ヒト) / Spodoptera exigua (シロイチモジヨトウ)手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 3.9 Å 詳細 データ登録者Eck MJ / Jeon H / Park E / Rawson S 資金援助 米国, 3件 詳細 詳細を隠すOrganization Grant number 国 National Institutes of Health/National Cancer Institute (NIH/NCI) P50CA165962 米国 National Institutes of Health/National Cancer Institute (NIH/NCI) R35CA242461 米国 National Institutes of Health/National Cancer Institute (NIH/NCI) R50CA220830 米国
引用ジャーナル : Nat Commun / 年 : 2023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. 履歴 登録 2022年6月24日 - ヘッダ(付随情報) 公開 2023年7月5日 - マップ公開 2023年7月5日 - 更新 2023年8月9日 - 現状 2023年8月9日 処理サイト : RCSB / 状態 : 公開
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