登録情報 データベース : EMDB / ID : EMD-22857 構造の表示 ダウンロードとリンクタイトル Structure of a ternary KRas(G13D)-SOS complex マップデータ 詳細 試料複合体 : A ternary complex of KRas(G13D) and SOScatタンパク質・ペプチド : GTPase KRasタンパク質・ペプチド : Son of sevenless homolog 1リガンド : PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTERリガンド : MAGNESIUM ION 詳細 キーワード Ras / Sos / GTPase / HYDROLASE-SIGNALING PROTEIN complex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
midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / regulation of T cell differentiation in thymus / GTPase complex / positive regulation of small GTPase mediated signal transduction / Interleukin-15 signaling ... midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / heart trabecula morphogenesis / regulation of T cell differentiation in thymus / GTPase complex / positive regulation of small GTPase mediated signal transduction / Interleukin-15 signaling / Activation of RAC1 / blood vessel morphogenesis / forebrain astrocyte development / positive regulation of epidermal growth factor receptor signaling pathway / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / epidermal growth factor receptor binding / epithelial tube branching involved in lung morphogenesis / Regulation of KIT signaling / type I pneumocyte differentiation / leukocyte migration / regulation of T cell proliferation / NRAGE signals death through JNK / roof of mouth development / Rac protein signal transduction / eyelid development in camera-type eye / skeletal muscle cell differentiation / positive regulation of Rac protein signal transduction / Signaling by RAS GAP mutants / Signaling by RAS GTPase mutants / Activation of RAS in B cells / Fc-epsilon receptor signaling pathway / GRB2:SOS provides linkage to MAPK signaling for Integrins / B cell homeostasis / neurotrophin TRK receptor signaling pathway / RAS signaling downstream of NF1 loss-of-function variants / RUNX3 regulates p14-ARF / SOS-mediated signalling / RET signaling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / hair follicle development / SHC1 events in ERBB4 signaling / Signalling to RAS / fibroblast growth factor receptor signaling pathway / SHC-related events triggered by IGF1R / glial cell proliferation / Activated NTRK2 signals through FRS2 and FRS3 / Role of LAT2/NTAL/LAB on calcium mobilization / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / Interleukin receptor SHC signaling / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Schwann cell development / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / SHC-mediated cascade:FGFR1 / Erythropoietin activates RAS / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / positive regulation of glial cell proliferation / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / FRS-mediated FGFR4 signaling / Signaling by FGFR3 in disease / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / Signaling by FGFR2 in disease / striated muscle cell differentiation / GRB2 events in EGFR signaling / SHC1 events in EGFR signaling / RAC1 GTPase cycle / EGFR Transactivation by Gastrin / Signaling by FLT3 fusion proteins / FLT3 Signaling / myelination / Ras activation upon Ca2+ influx through NMDA receptor / Signaling by FGFR1 in disease / GRB2 events in ERBB2 signaling / NCAM signaling for neurite out-growth / CD209 (DC-SIGN) signaling / SHC1 events in ERBB2 signaling / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / FCERI mediated Ca+2 mobilization / Insulin receptor signalling cascade / GTPase activator activity / guanyl-nucleotide exchange factor activity / insulin-like growth factor receptor signaling pathway / small monomeric GTPase / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants / G protein activity 類似検索 - 分子機能 Ras guanine-nucleotide exchange factor, conserved site / Ras Guanine-nucleotide exchange factors domain signature. / RasGEF N-terminal motif / Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif / Ras-like guanine nucleotide exchange factor, N-terminal / Ras guanine-nucleotide exchange factors N-terminal domain profile. / Ras-like guanine nucleotide exchange factor / Ras guanine-nucleotide exchange factor, catalytic domain superfamily / Ras guanine nucleotide exchange factor domain superfamily / RasGEF domain ... Ras guanine-nucleotide exchange factor, conserved site / Ras Guanine-nucleotide exchange factors domain signature. / RasGEF N-terminal motif / Guanine nucleotide exchange factor for Ras-like GTPases; N-terminal motif / Ras-like guanine nucleotide exchange factor, N-terminal / Ras guanine-nucleotide exchange factors N-terminal domain profile. / Ras-like guanine nucleotide exchange factor / Ras guanine-nucleotide exchange factor, catalytic domain superfamily / Ras guanine nucleotide exchange factor domain superfamily / RasGEF domain / Ras guanine-nucleotide exchange factors catalytic domain profile. / Guanine nucleotide exchange factor for Ras-like small GTPases / Ras guanine-nucleotide exchange factors catalytic domain / Dbl homology (DH) domain superfamily / RhoGEF domain / Guanine nucleotide exchange factor for Rho/Rac/Cdc42-like GTPases / Dbl homology (DH) domain / Dbl homology (DH) domain profile. / Small GTPase, Ras-type / small GTPase Ras family profile. / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / PH domain / PH domain profile. / Pleckstrin homology domain. / Pleckstrin homology domain / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Rab subfamily of small GTPases / Histone-fold / Small GTP-binding protein domain / PH-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase 類似検索 - ドメイン・相同性生物種 Homo sapiens (ヒト)手法 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度 : 3.47 Å 詳細 データ登録者Liu C / Moghadamchargari Z 資金援助 米国, 1件 詳細 詳細を隠すOrganization Grant number 国 National Institutes of Health/National Cancer Institute (NIH/NCI) RO1GM121751 米国
引用ジャーナル : Proc Natl Acad Sci U S A / 年 : 2021タイトル : Molecular assemblies of the catalytic domain of SOS with KRas and oncogenic mutants.著者 : Zahra Moghadamchargari / Mehdi Shirzadeh / Chang Liu / Samantha Schrecke / Charles Packianathan / David H Russell / Minglei Zhao / Arthur Laganowsky / 要旨 : Ras is regulated by a specific guanine nucleotide exchange factor Son of Sevenless (SOS), which facilitates the exchange of inactive, GDP-bound Ras with GTP. The catalytic activity of SOS is also ... Ras is regulated by a specific guanine nucleotide exchange factor Son of Sevenless (SOS), which facilitates the exchange of inactive, GDP-bound Ras with GTP. The catalytic activity of SOS is also allosterically modulated by an active Ras (Ras-GTP). However, it remains poorly understood how oncogenic Ras mutants interact with SOS and modulate its activity. Here, native ion mobility-mass spectrometry is employed to monitor the assembly of the catalytic domain of SOS (SOS) with KRas and three cancer-associated mutants (G12C, G13D, and Q61H), leading to the discovery of different molecular assemblies and distinct conformers of SOS engaging KRas. We also find KRas exhibits high affinity for SOS and is a potent allosteric modulator of its activity. A structure of the KRas•SOS complex was determined using cryogenic electron microscopy providing insight into the enhanced affinity of the mutant protein. In addition, we find that KRas-GTP can allosterically increase the nucleotide exchange rate of KRas at the active site more than twofold compared to KRas-GTP. Furthermore, small-molecule Ras•SOS disruptors fail to dissociate KRas•SOS complexes, underscoring the need for more potent disruptors. Taken together, a better understanding of the interaction between oncogenic Ras mutants and SOS will provide avenues for improved therapeutic interventions. 履歴 登録 2020年10月15日 - ヘッダ(付随情報) 公開 2021年3月31日 - マップ公開 2021年3月31日 - 更新 2024年3月6日 - 現状 2024年3月6日 処理サイト : RCSB / 状態 : 公開
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