+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 9axa | ||||||
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タイトル | CryoEM structure of activated CRAF/MEK/14-3-3 complex with NST-628 | ||||||
要素 |
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キーワード | TRANSFERASE (転移酵素) / Inhibitor / complex / SIGNALING PROTEIN | ||||||
機能・相同性 | 機能・相同性情報 death-inducing signaling complex assembly / epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / intermediate filament cytoskeleton organization / placenta blood vessel development / regulation of axon regeneration / MAPキナーゼキナーゼ / type B pancreatic cell proliferation / labyrinthine layer development / MAP-kinase scaffold activity ...death-inducing signaling complex assembly / epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / intermediate filament cytoskeleton organization / placenta blood vessel development / regulation of axon regeneration / MAPキナーゼキナーゼ / type B pancreatic cell proliferation / labyrinthine layer development / MAP-kinase scaffold activity / cerebellar cortex formation / regulation of Rho protein signal transduction / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Signaling by MAP2K mutants / Rap1 signalling / regulation of cell motility / insulin secretion involved in cellular response to glucose stimulus / regulation of Golgi inheritance / 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 / IFNG signaling activates MAPKs / Frs2-mediated activation / GP1b-IX-V activation signalling / protein kinase activator activity / ERBB2-ERBB3 signaling pathway / regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / ケラチン / regulation of cell differentiation / endodermal cell differentiation / face development / MAPK3 (ERK1) activation / 仮足 / somatic stem cell population maintenance / Bergmann glial cell differentiation / neurotrophin TRK receptor signaling pathway / thyroid gland development / MAP kinase kinase activity / グルタチオン-S-トランスフェラーゼ / Uptake and function of anthrax toxins / glutathione transferase activity / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / extrinsic apoptotic signaling pathway via death domain receptors / MAP kinase kinase kinase activity / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation / establishment of skin barrier / negative regulation of protein-containing complex assembly / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Schwann cell development / type II interferon-mediated signaling pathway / protein kinase A signaling / negative regulation of stem cell proliferation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / RHO GTPases activate PKNs / keratinocyte differentiation / ERK1 and ERK2 cascade / activation of adenylate cyclase activity / response to muscle stretch / 髄鞘 / protein export from nucleus / negative regulation of innate immune response / protein serine/threonine/tyrosine kinase activity / CD209 (DC-SIGN) signaling / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / protein sequestering activity / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / insulin-like growth factor receptor signaling pathway / release of cytochrome c from mitochondria / positive regulation of protein export from nucleus / thymus development / Signal transduction by L1 / stem cell proliferation / 運動性 / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / negative regulation of protein kinase activity / RAF activation / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / wound healing / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of protein serine/threonine kinase activity / Stimuli-sensing channels / neuron differentiation / 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 類似検索 - 分子機能 | ||||||
生物種 | Homo sapiens (ヒト) | ||||||
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: 4.36 Å | ||||||
データ登録者 | Quade, B. / Cohen, S.E. / Huang, X. | ||||||
資金援助 | 1件
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引用 | ジャーナル: Cancer Discov / 年: 2024 タイトル: The pan-RAF-MEK non degrading molecular glue NST-628 is a potent and brain penetrant inhibitor of the RAS-MAPK pathway with activity across diverse RAS- and RAF-driven cancers. 著者: Meagan B Ryan / Bradley Quade / Natasha Schenk / Zhong Fang / Marshall Zingg / Steven E Cohen / Brooke M Swalm / Chun Li / Aysegul Ozen / Chaoyang Ye / Maria Stella Ritorto / Xin Huang / ...著者: Meagan B Ryan / Bradley Quade / Natasha Schenk / Zhong Fang / Marshall Zingg / Steven E Cohen / Brooke M Swalm / Chun Li / Aysegul Ozen / Chaoyang Ye / Maria Stella Ritorto / Xin Huang / Arvin C Dar / Yongxin Han / Klaus P Hoeflich / Michael Hale / Margit Hagel / 要旨: Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents ...Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analysis of RAF-MEK complexes show that NST-628 engages all isoforms of RAFand prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies , NST-628 is positioned to make an impact clinically in an areas of unmet patient need. | ||||||
履歴 |
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-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
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-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 9axa.cif.gz | 304.1 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb9axa.ent.gz | 表示 | PDB形式 | |
PDBx/mmJSON形式 | 9axa.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
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/ax/9axa ftp://data.pdbj.org/pub/pdb/validation_reports/ax/9axa | HTTPS FTP |
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-関連構造データ
関連構造データ | 43931MC 9axcC 9axhC 9axmC 9axxC 9axyC 9ay7C 9ayaC 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 (文献) |
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類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-リンク
-集合体
登録構造単位 |
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-要素
#1: タンパク質 | 分子量: 64798.465 Da / 分子数: 2 / 変異: Y340D Y341D / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: RAF1, RAF / 発現宿主: Homo sapiens (ヒト) 参照: UniProt: P08515, UniProt: P04049, グルタチオン-S-トランスフェラーゼ, non-specific serine/threonine protein kinase #2: タンパク質 | 分子量: 43518.988 Da / 分子数: 2 / 変異: S218A S222A / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: MAP2K1, MEK1, PRKMK1 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: Q02750, MAPキナーゼキナーゼ #3: タンパク質 | 分子量: 27807.064 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: SFN, HME1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: P31947 #4: 化合物 | 分子量: 488.464 Da / 分子数: 2 / 由来タイプ: 合成 / 式: C22H18F2N4O5S / タイプ: SUBJECT OF INVESTIGATION 研究の焦点であるリガンドがあるか | Y | |
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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 |
-試料調製
構成要素 | 名称: CRAF/MEK/14-3-3 complex with NST-628 / タイプ: COMPLEX / Entity ID: #1-#3 / 由来: RECOMBINANT |
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由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
緩衝液 | pH: 7.5 |
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES |
急速凍結 | 凍結剤: ETHANE |
-電子顕微鏡撮影
顕微鏡 | モデル: TFS GLACIOS |
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電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 200 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELDBright-field microscopy / 最大 デフォーカス(公称値): 2500 nm / 最小 デフォーカス(公称値): 1000 nm |
撮影 | 電子線照射量: 50 e/Å2 フィルム・検出器のモデル: FEI FALCON IV (4k x 4k) |
-解析
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3次元再構成 | 解像度: 4.36 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 83248 / 対称性のタイプ: POINT |
精密化 | 交差検証法: NONE |