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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: 8er7 | ||||||
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タイトル | FKBP12-FRB in Complex with Compound 12 | ||||||
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![]() | COMPLEX (ISOMERASE/KINASE) / Antitumor / mTORC1 / COMPLEX (ISOMERASE-KINASE) complex | ||||||
機能・相同性 | ![]() regulation of nucleobase-containing compound metabolic process / positive regulation of response to stimulus / response to chemical / regulation of cellular response to stress / macrolide binding / activin receptor binding / TORC1 complex / cytoplasmic side of membrane / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / signaling receptor inhibitor activity ...regulation of nucleobase-containing compound metabolic process / positive regulation of response to stimulus / response to chemical / regulation of cellular response to stress / macrolide binding / activin receptor binding / TORC1 complex / cytoplasmic side of membrane / regulation of skeletal muscle contraction by regulation of release of sequestered calcium ion / signaling receptor inhibitor activity / transforming growth factor beta receptor binding / TGFBR1 LBD Mutants in Cancer / response to stress / type I transforming growth factor beta receptor binding / negative regulation of activin receptor signaling pathway / heart trabecula formation / terminal cisterna / ryanodine receptor complex / I-SMAD binding / regulation of amyloid precursor protein catabolic process / protein maturation by protein folding / ventricular cardiac muscle tissue morphogenesis / 'de novo' protein folding / FK506 binding / channel regulator activity / TGF-beta receptor signaling activates SMADs / mTORC1-mediated signalling / protein peptidyl-prolyl isomerization / Calcineurin activates NFAT / regulation of ryanodine-sensitive calcium-release channel activity / regulation of immune response / heart morphogenesis / supramolecular fiber organization / sarcoplasmic reticulum membrane / T cell activation / positive regulation of protein metabolic process / TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition) / sarcoplasmic reticulum / peptidylprolyl isomerase / peptidyl-prolyl cis-trans isomerase activity / calcium ion transmembrane transport / negative regulation of transforming growth factor beta receptor signaling pathway / Z disc / regulation of protein localization / SARS-CoV-1 activates/modulates innate immune responses / protein folding / positive regulation of protein binding / protein refolding / peptidyl-serine phosphorylation / positive regulation of canonical NF-kappaB signal transduction / transmembrane transporter binding / amyloid fibril formation / Potential therapeutics for SARS / non-specific serine/threonine protein kinase / protein serine/threonine kinase activity / protein-containing complex binding / ATP binding / membrane / cytosol / cytoplasm 類似検索 - 分子機能 | ||||||
生物種 | ![]() | ||||||
手法 | ![]() ![]() ![]() | ||||||
![]() | Tomlinson, A.C.A. / Yano, J.K. | ||||||
資金援助 | ![]()
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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 | ![]() | 298.8 KB | 表示 | ![]() |
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PDB形式 | ![]() | 219.5 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
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-関連構造データ
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リンク
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集合体
登録構造単位 | ![]()
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単位格子 |
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要素
#1: タンパク質 | 分子量: 11923.586 Da / 分子数: 3 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() #2: タンパク質 | 分子量: 11388.987 Da / 分子数: 3 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() 参照: UniProt: B1AKP8, non-specific serine/threonine protein kinase #3: 化合物 | #4: 化合物 | #5: 水 | ChemComp-HOH / | 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: ![]() |
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試料調製
結晶 | マシュー密度: 4.09 Å3/Da / 溶媒含有率: 69.94 % |
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結晶化 | 温度: 293 K / 手法: 蒸気拡散法, ハンギングドロップ法 / 詳細: 3.0-3.3 M sodium formate and 0.1 M HEPES pH 7.0-7.5 / PH範囲: 7.0-7.5 |
-データ収集
回折 | 平均測定温度: 100 K / Serial crystal experiment: N |
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放射光源 | 由来: ![]() ![]() ![]() |
検出器 | タイプ: DECTRIS PILATUS 2M-F / 検出器: PIXEL / 日付: 2017年10月23日 |
放射 | プロトコル: SINGLE WAVELENGTH / 単色(M)・ラウエ(L): M / 散乱光タイプ: x-ray |
放射波長 | 波長: 0.99993 Å / 相対比: 1 |
反射 | 解像度: 3.07→45.91 Å / Num. obs: 21756 / % possible obs: 95.8 % / 冗長度: 4.2 % / Biso Wilson estimate: 92.86 Å2 / Rrim(I) all: 0.082 / Rsym value: 0.072 / Net I/σ(I): 11.06 |
反射 シェル | 解像度: 3.07→3.32 Å / Mean I/σ(I) obs: 2.88 / Num. unique obs: 2054 / Rrim(I) all: 0.0486 / Rsym value: 0.0427 |
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解析
ソフトウェア |
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精密化 | 構造決定の手法: ![]() 開始モデル: 1FAP 解像度: 3.07→45.91 Å / SU ML: 0.3504 / 交差検証法: FREE R-VALUE / σ(F): 1.36 / 位相誤差: 32.8029 立体化学のターゲット値: GeoStd + Monomer Library + CDL v1.2
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溶媒の処理 | 減衰半径: 0.9 Å / VDWプローブ半径: 1.1 Å / 溶媒モデル: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
原子変位パラメータ | Biso mean: 119.85 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
精密化ステップ | サイクル: LAST / 解像度: 3.07→45.91 Å
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拘束条件 |
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LS精密化 シェル |
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精密化 TLS | 手法: refined / Refine-ID: X-RAY DIFFRACTION
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精密化 TLSグループ |
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