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データを開く
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基本情報
登録情報 | データベース: PDB / ID: 8era | ||||||
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タイトル | RMC-5552 in complex with mTORC1 and FKBP12 | ||||||
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![]() | COMPLEX (ISOMERASE/KINASE) / Antitumor / mTORC1 / COMPLEX (ISOMERASE-KINASE) complex | ||||||
機能・相同性 | ![]() positive regulation of cytoplasmic translational initiation / positive regulation of pentose-phosphate shunt / RNA polymerase III type 1 promoter sequence-specific DNA binding / RNA polymerase III type 2 promoter sequence-specific DNA binding / T-helper 1 cell lineage commitment / regulation of locomotor rhythm / positive regulation of wound healing, spreading of epidermal cells / cellular response to leucine starvation / regulation of membrane permeability / heart valve morphogenesis ...positive regulation of cytoplasmic translational initiation / positive regulation of pentose-phosphate shunt / RNA polymerase III type 1 promoter sequence-specific DNA binding / RNA polymerase III type 2 promoter sequence-specific DNA binding / T-helper 1 cell lineage commitment / regulation of locomotor rhythm / positive regulation of wound healing, spreading of epidermal cells / cellular response to leucine starvation / regulation of membrane permeability / heart valve morphogenesis / TFIIIC-class transcription factor complex binding / negative regulation of lysosome organization / macrolide binding / RNA polymerase III type 3 promoter sequence-specific DNA binding / TORC2 complex / activin receptor binding / TORC1 complex / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / cytoplasmic side of membrane / regulation of autophagosome assembly / calcineurin-NFAT signaling cascade / nucleus localization / TORC1 signaling / voluntary musculoskeletal movement / positive regulation of odontoblast differentiation / regulation of osteoclast differentiation / positive regulation of keratinocyte migration / signaling receptor inhibitor activity / transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / cellular response to L-leucine / MTOR signalling / Amino acids regulate mTORC1 / cellular response to nutrient / energy reserve metabolic process / type I transforming growth factor beta receptor binding / Energy dependent regulation of mTOR by LKB1-AMPK / negative regulation of activin receptor signaling pathway / negative regulation of cell size / heart trabecula formation / ruffle organization / protein serine/threonine kinase inhibitor activity / positive regulation of osteoclast differentiation / cellular response to osmotic stress / terminal cisterna / ryanodine receptor complex / I-SMAD binding / enzyme-substrate adaptor activity / negative regulation of protein localization to nucleus / anoikis / regulation of amyloid precursor protein catabolic process / cardiac muscle cell development / positive regulation of transcription by RNA polymerase III / protein maturation by protein folding / negative regulation of calcineurin-NFAT signaling cascade / ventricular cardiac muscle tissue morphogenesis / 'de novo' protein folding / regulation of myelination / regulation of cell size / Macroautophagy / negative regulation of phosphoprotein phosphatase activity / positive regulation of oligodendrocyte differentiation / negative regulation of macroautophagy / FK506 binding / positive regulation of actin filament polymerization / lysosome organization / positive regulation of myotube differentiation / protein kinase activator activity / behavioral response to pain / oligodendrocyte differentiation / TGF-beta receptor signaling activates SMADs / Constitutive Signaling by AKT1 E17K in Cancer / mTORC1-mediated signalling / germ cell development / CD28 dependent PI3K/Akt signaling / cellular response to nutrient levels / positive regulation of phosphoprotein phosphatase activity / social behavior / Calcineurin activates NFAT / HSF1-dependent transactivation / regulation of immune response / positive regulation of TOR signaling / TOR signaling / neuronal action potential / positive regulation of translational initiation / response to amino acid / positive regulation of G1/S transition of mitotic cell cycle / regulation of macroautophagy / endomembrane system / 'de novo' pyrimidine nucleobase biosynthetic process / protein peptidyl-prolyl isomerization / positive regulation of epithelial to mesenchymal transition / positive regulation of lamellipodium assembly / positive regulation of lipid biosynthetic process / heart morphogenesis / cardiac muscle contraction / supramolecular fiber organization / regulation of cellular response to heat / regulation of ryanodine-sensitive calcium-release channel activity / positive regulation of stress fiber assembly 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: 2.86 Å | ||||||
![]() | Tomlinson, A.C.A. / Yano, J.K. | ||||||
資金援助 | 1件
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![]() | ![]() タイトル: Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors. 著者: G Leslie Burnett / Yu C Yang / James B Aggen / Jennifer Pitzen / Micah K Gliedt / Chris M Semko / Abby Marquez / James W Evans / Gang Wang / Walter S Won / Aidan C A Tomlinson / Gert Kiss / ...著者: G Leslie Burnett / Yu C Yang / James B Aggen / Jennifer Pitzen / Micah K Gliedt / Chris M Semko / Abby Marquez / James W Evans / Gang Wang / Walter S Won / Aidan C A Tomlinson / Gert Kiss / Christos Tzitzilonis / Arun P Thottumkara / James Cregg / Kevin T Mellem / Jong S Choi / Julie C Lee / Yongyuan Zhao / Bianca J Lee / Justin G Meyerowitz / John E Knox / Jingjing Jiang / Zhican Wang / David Wildes / Zhengping Wang / Mallika Singh / Jacqueline A M Smith / Adrian L Gill / ![]() 要旨: Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of ...Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of "bi-steric inhibitors" that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRAS shows increased antitumor activity in a preclinical model of mutant NSCLC that exhibits resistance to KRAS inhibitor monotherapy. #1: ![]() タイトル: Towards automated crystallographic structure refinement with phenix.refine. 著者: Afonine, P.V. / Grosse-Kunstleve, R.W. / Echols, N. / Headd, J.J. / Moriarty, N.W. / Mustyakimov, M. / Terwilliger, T.C. / Urzhumtsev, A. / Zwart, P.H. / Adams, P.D. | ||||||
履歴 |
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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ダウンロード
PDBx/mmCIF形式 | ![]() | 797.5 KB | 表示 | ![]() |
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PDB形式 | ![]() | 584.2 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 1.2 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.3 MB | 表示 | |
XML形式データ | ![]() | 95.2 KB | 表示 | |
CIF形式データ | ![]() | 148 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 | ![]() 28551MC ![]() 8er6C ![]() 8er7C 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 | 類似検索 - 機能・相同性 ![]() |
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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
-タンパク質 , 4種, 4分子 ABCY
#1: タンパク質 | 分子量: 289257.969 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() 参照: UniProt: P42345, non-specific serine/threonine protein kinase |
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#2: タンパク質 | 分子量: 11923.586 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
#3: タンパク質 | 分子量: 35910.090 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
#4: タンパク質 | 分子量: 149200.016 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() |
-非ポリマー , 2種, 2分子 ![](data/chem/img/XZ9.gif)
![](data/chem/img/XYU.gif)
![](data/chem/img/XYU.gif)
#5: 化合物 | ChemComp-XZ9 / |
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#6: 化合物 | ChemComp-XYU / ( |
-詳細
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: 2D ARRAY / 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: RMC-5552-mTORC1-FKBP12 / タイプ: COMPLEX / Entity ID: #1-#4 / 由来: RECOMBINANT |
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由来(天然) | 生物種: ![]() |
由来(組換発現) | 生物種: ![]() |
緩衝液 | pH: 8 |
試料 | 濃度: 5 mg/ml / 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 |
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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 / 最大 デフォーカス(公称値): 3000 nm / 最小 デフォーカス(公称値): 1000 nm |
撮影 | 電子線照射量: 30 e/Å2 フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
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解析
ソフトウェア |
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CTF補正 | タイプ: NONE | ||||||||||||||||||||||||
3次元再構成 | 解像度: 2.86 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 805027 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
精密化 | 交差検証法: NONE | ||||||||||||||||||||||||
拘束条件 |
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