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 / negative regulation of homotypic cell-cell adhesion / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / positive regulation of endodermal cell differentiation / regulation of vascular associated smooth muscle contraction / CD4-positive, alpha-beta T cell differentiation / positive regulation of axon regeneration / mitogen-activated protein kinase kinase / Golgi inheritance / placenta blood vessel development ... epithelial cell proliferation involved in lung morphogenesis / negative regulation of homotypic cell-cell adhesion / negative regulation of hypoxia-induced intrinsic apoptotic signaling pathway / positive regulation of endodermal cell differentiation / regulation of vascular associated smooth muscle contraction / CD4-positive, alpha-beta T cell differentiation / positive regulation of axon regeneration / mitogen-activated protein kinase kinase / Golgi inheritance / placenta blood vessel development / MAP-kinase scaffold activity / positive regulation of muscle contraction / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / negative regulation of synaptic vesicle exocytosis / labyrinthine layer development / regulation of axon regeneration / cerebellar cortex formation / melanosome transport / Signalling to p38 via RIT and RIN / type B pancreatic cell proliferation / head morphogenesis / ARMS-mediated activation / myeloid progenitor cell differentiation / endothelial cell apoptotic process / Signaling by MAP2K mutants / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / positive regulation of D-glucose transmembrane transport / negative regulation of fibroblast migration / vesicle transport along microtubule / establishment of protein localization to membrane / positive regulation of axonogenesis / positive regulation of Ras protein signal transduction / regulation of Golgi inheritance / central nervous system neuron differentiation / mitogen-activated protein kinase kinase kinase binding / triglyceride homeostasis / regulation of T cell differentiation / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / Frs2-mediated activation / stress fiber assembly / MAPK3 (ERK1) activation / ERBB2-ERBB3 signaling pathway / regulation of neurotransmitter receptor localization to postsynaptic specialization membrane / endodermal cell differentiation / face development / MAP kinase kinase activity / positive regulation of ATP biosynthetic process / Bergmann glial cell differentiation / Uptake and function of anthrax toxins / thyroid gland development / synaptic vesicle exocytosis / neuron projection morphogenesis / protein kinase activator activity / somatic stem cell population maintenance / positive regulation of protein serine/threonine kinase activity / positive regulation of peptidyl-serine phosphorylation / MAP kinase kinase kinase activity / response to axon injury / negative regulation of endothelial cell apoptotic process / postsynaptic modulation of chemical synaptic transmission / Schwann cell development / keratinocyte differentiation / MAP3K8 (TPL2)-dependent MAPK1/3 activation / positive regulation of stress fiber assembly / ERK1 and ERK2 cascade / myelination / positive regulation of autophagy / positive regulation of substrate adhesion-dependent cell spreading / protein serine/threonine/tyrosine kinase activity / substrate adhesion-dependent cell spreading / dendrite cytoplasm / insulin-like growth factor receptor signaling pathway / cellular response to calcium ion / response to glucocorticoid / thymus development / protein serine/threonine kinase activator activity / animal organ morphogenesis / Signal transduction by L1 / small monomeric GTPase / Spry regulation of FGF signaling / cell motility / RAF activation / positive regulation of transcription elongation by RNA polymerase II / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / small GTPase binding / Negative regulation of MAPK pathway / centriolar satellite / long-term synaptic potentiation / cellular response to xenobiotic stimulus / epidermal growth factor receptor signaling pathway / neuron differentiation / chemotaxis / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants 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 Rab domain profile. / Small GTPase Rho domain 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 Rab domain profile. / Small GTPase Rho domain 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 domain 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. / Protein kinase domain / Serine/Threonine protein kinases, catalytic 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 small monomeric GTPase / 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 2025年5月14日 - 現状 2025年5月14日 処理サイト : RCSB / 状態 : 公開
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