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基本情報
登録情報 | データベース: PDB / ID: 7kfz | ||||||
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タイトル | Structure of a ternary KRas(G13D)-SOS complex | ||||||
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![]() | HYDROLASE/SIGNALING PROTEIN / Ras / Sos / GTPase / HYDROLASE-SIGNALING PROTEIN complex | ||||||
機能・相同性 | ![]() midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / eyelid development in camera-type eye / heart trabecula morphogenesis / regulation of T cell differentiation in thymus / GTPase complex / positive regulation of small GTPase mediated signal transduction ...midbrain morphogenesis / regulation of pro-B cell differentiation / vitellogenesis / pericardium morphogenesis / cardiac atrium morphogenesis / eyelid development in camera-type eye / 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 / Signaling by LTK / forebrain astrocyte development / hair follicle development / positive regulation of epidermal growth factor receptor signaling pathway / negative regulation of epithelial cell differentiation / regulation of synaptic transmission, GABAergic / Regulation of KIT signaling / epidermal growth factor receptor binding / type I pneumocyte differentiation / epithelial tube branching involved in lung morphogenesis / leukocyte migration / regulation of T cell proliferation / NRAGE signals death through JNK / roof of mouth development / Rac protein signal transduction / 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 / positive regulation of glial cell proliferation / GRB2:SOS provides linkage to MAPK signaling for Integrins / B cell homeostasis / RAS signaling downstream of NF1 loss-of-function variants / neurotrophin TRK receptor signaling pathway / RUNX3 regulates p14-ARF / SOS-mediated signalling / RET signaling / Activated NTRK3 signals through RAS / Activated NTRK2 signals through RAS / SHC1 events in ERBB4 signaling / GRB2 events in EGFR signaling / EGFR Transactivation by Gastrin / SHC1 events in EGFR signaling / Signalling to RAS / fibroblast growth factor receptor signaling pathway / GRB2 events in ERBB2 signaling / SHC-related events triggered by IGF1R / Activated NTRK2 signals through FRS2 and FRS3 / glial cell proliferation / Role of LAT2/NTAL/LAB on calcium mobilization / Interleukin receptor SHC signaling / Signal attenuation / Estrogen-stimulated signaling through PRKCZ / SHC1 events in ERBB2 signaling / SHC-mediated cascade:FGFR3 / MET activates RAS signaling / Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants / Signaling by PDGFRA extracellular domain mutants / Schwann cell development / SHC-mediated cascade:FGFR2 / PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases / SHC-mediated cascade:FGFR4 / Signaling by FGFR4 in disease / Erythropoietin activates RAS / SHC-mediated cascade:FGFR1 / protein-membrane adaptor activity / FRS-mediated FGFR3 signaling / Signaling by CSF3 (G-CSF) / Signaling by FLT3 ITD and TKD mutants / homeostasis of number of cells within a tissue / FRS-mediated FGFR2 signaling / Signaling by FGFR3 in disease / FRS-mediated FGFR4 signaling / p38MAPK events / Tie2 Signaling / FRS-mediated FGFR1 signaling / striated muscle cell differentiation / Signaling by FGFR2 in disease / Signaling by FLT3 fusion proteins / RAC1 GTPase cycle / FLT3 Signaling / Ras activation upon Ca2+ influx through NMDA receptor / myelination / Signaling by FGFR1 in disease / CD209 (DC-SIGN) signaling / NCAM signaling for neurite out-growth / Downstream signal transduction / Constitutive Signaling by Overexpressed ERBB2 / FCERI mediated Ca+2 mobilization / Insulin receptor signalling cascade / GTPase activator activity / insulin-like growth factor receptor signaling pathway / Signaling by ERBB2 TMD/JMD mutants / small monomeric GTPase / Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants 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: 3.47 Å | ||||||
![]() | Liu, C. / Moghadamchargari, Z. / Laganowsky, A. / Zhao, M. | ||||||
資金援助 | ![]()
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![]() | ![]() 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. | ||||||
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構造の表示
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構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 159.3 KB | 表示 | ![]() |
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PDB形式 | ![]() | 121.4 KB | 表示 | ![]() |
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-検証レポート
文書・要旨 | ![]() | 1.1 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.1 MB | 表示 | |
XML形式データ | ![]() | 33.8 KB | 表示 | |
CIF形式データ | ![]() | 52.4 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 22857MC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 ( |
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類似構造データ | |
電子顕微鏡画像生データ | ![]() Data size: 3.7 TB Data #1: Unaligned raw movie of SOS-KRas (G13D) complex [micrographs - multiframe]) |
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リンク
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集合体
登録構造単位 | ![]()
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要素
#1: タンパク質 | 分子量: 19386.848 Da / 分子数: 2 / 変異: G13D / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() #2: タンパク質 | | 分子量: 57449.691 Da / 分子数: 1 / Fragment: UNP residues 564-1049 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() #3: 化合物 | ChemComp-GNP / | #4: 化合物 | ChemComp-MG / | 研究の焦点であるリガンドがあるか | N | |
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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: A ternary complex of KRas(G13D) and SOScat / タイプ: COMPLEX / Entity ID: #1-#2 / 由来: RECOMBINANT |
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分子量 | 値: 0.0967 MDa / 実験値: YES |
由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() ![]() |
緩衝液 | pH: 7.4 |
試料 | 濃度: 8.6 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE / 湿度: 100 % / 凍結前の試料温度: 281 K |
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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: BRIGHT FIELD / 倍率(公称値): 105000 X / 最大 デフォーカス(公称値): 2500 nm / 最小 デフォーカス(公称値): 800 nm / Cs: 2.7 mm |
撮影 | 電子線照射量: 65 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) 実像数: 5202 |
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解析
ソフトウェア | 名称: PHENIX / バージョン: 1.18.2_3874: / 分類: 精密化 | ||||||||||||||||||||||||||||||||
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EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING ONLY | ||||||||||||||||||||||||||||||||
粒子像の選択 | 選択した粒子像数: 5749548 | ||||||||||||||||||||||||||||||||
対称性 | 点対称性: C1 (非対称) | ||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 3.47 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 1021288 / 対称性のタイプ: POINT | ||||||||||||||||||||||||||||||||
原子モデル構築 | B value: 50 / プロトコル: AB INITIO MODEL / 空間: REAL | ||||||||||||||||||||||||||||||||
原子モデル構築 | PDB-ID: 1XD2 Accession code: 1XD2 / Source name: PDB / タイプ: experimental model | ||||||||||||||||||||||||||||||||
拘束条件 |
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