+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 6bcx | ||||||
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タイトル | mTORC1 structure refined to 3.0 angstroms | ||||||
要素 |
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キーワード | TRANSFERASE / PIKK | ||||||
機能・相同性 | 機能・相同性情報 RNA polymerase III type 2 promoter sequence-specific DNA binding / RNA polymerase III type 1 promoter sequence-specific DNA binding / positive regulation of cytoplasmic translational initiation / Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S / regulation of locomotor rhythm / T-helper 1 cell lineage commitment / positive regulation of pentose-phosphate shunt / positive regulation of wound healing, spreading of epidermal cells / eukaryotic initiation factor 4E binding / TORC2 complex ...RNA polymerase III type 2 promoter sequence-specific DNA binding / RNA polymerase III type 1 promoter sequence-specific DNA binding / positive regulation of cytoplasmic translational initiation / Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S / regulation of locomotor rhythm / T-helper 1 cell lineage commitment / positive regulation of pentose-phosphate shunt / positive regulation of wound healing, spreading of epidermal cells / eukaryotic initiation factor 4E binding / TORC2 complex / cellular response to leucine starvation / TFIIIC-class transcription factor complex binding / regulation of membrane permeability / negative regulation of lysosome organization / heart valve morphogenesis / nucleus localization / RNA polymerase III type 3 promoter sequence-specific DNA binding / TORC1 complex / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / calcineurin-NFAT signaling cascade / voluntary musculoskeletal movement / TORC1 signaling / regulation of osteoclast differentiation / positive regulation of odontoblast differentiation / positive regulation of keratinocyte migration / cellular response to L-leucine / Amino acids regulate mTORC1 / MTOR signalling / cellular response to nutrient / regulation of autophagosome assembly / cellular response to methionine / Energy dependent regulation of mTOR by LKB1-AMPK / energy reserve metabolic process / negative regulation of cell size / ruffle organization / positive regulation of osteoclast differentiation / cellular response to osmotic stress / protein serine/threonine kinase inhibitor activity / enzyme-substrate adaptor activity / negative regulation of protein localization to nucleus / anoikis / cardiac muscle cell development / positive regulation of transcription by RNA polymerase III / negative regulation of calcineurin-NFAT signaling cascade / regulation of myelination / positive regulation of actin filament polymerization / regulation of cell size / negative regulation of macroautophagy / positive regulation of oligodendrocyte differentiation / lysosome organization / Macroautophagy / positive regulation of myotube differentiation / protein kinase activator activity / behavioral response to pain / oligodendrocyte differentiation / Constitutive Signaling by AKT1 E17K in Cancer / mTORC1-mediated signalling / germ cell development / : / CD28 dependent PI3K/Akt signaling / social behavior / HSF1-dependent transactivation / neuronal action potential / positive regulation of TOR signaling / response to amino acid / TOR signaling / endomembrane system / 'de novo' pyrimidine nucleobase biosynthetic process / regulation of macroautophagy / positive regulation of translational initiation / positive regulation of G1/S transition of mitotic cell cycle / cellular response to nutrient levels / positive regulation of lamellipodium assembly / phagocytic vesicle / heart morphogenesis / positive regulation of lipid biosynthetic process / positive regulation of epithelial to mesenchymal transition / phosphorylation / cardiac muscle contraction / regulation of cellular response to heat / translation repressor activity / negative regulation of translational initiation / positive regulation of stress fiber assembly / cytoskeleton organization / 14-3-3 protein binding / positive regulation of endothelial cell proliferation / T cell costimulation / translation initiation factor binding / cellular response to amino acid starvation / cellular response to starvation / post-embryonic development / positive regulation of glycolytic process / negative regulation of autophagy / positive regulation of mitotic cell cycle / protein serine/threonine kinase activator activity / response to nutrient / response to nutrient levels / VEGFR2 mediated vascular permeability / regulation of signal transduction by p53 class mediator / positive regulation of peptidyl-threonine phosphorylation 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: 3.23 Å | ||||||
データ登録者 | Pavletich, N.P. / Yang, H. | ||||||
資金援助 | 米国, 1件
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引用 | ジャーナル: Nature / 年: 2017 タイトル: Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. 著者: Haijuan Yang / Xiaolu Jiang / Buren Li / Hyo J Yang / Meredith Miller / Angela Yang / Ankita Dhar / Nikola P Pavletich / 要旨: The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the ...The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 ångström cryo-electron microscopy structure of mTORC1 and the 3.4 ångström structure of activated RHEB-mTORC1. RHEB binds to mTOR distally from the kinase active site, yet causes a global conformational change that allosterically realigns active-site residues, accelerating catalysis. Cancer-associated hyperactivating mutations map to structural elements that maintain the inactive state, and we provide biochemical evidence that they mimic RHEB relieving auto-inhibition. We also present crystal structures of RAPTOR-TOS motif complexes that define the determinants of TOS recognition, of an mTOR FKBP12-rapamycin-binding (FRB) domain-substrate complex that establishes a second substrate-recruitment mechanism, and of a truncated mTOR-PRAS40 complex that reveals PRAS40 inhibits both substrate-recruitment sites. These findings help explain how mTORC1 selects its substrates, how its kinase activity is controlled, and how it is activated by cancer-associated mutations. | ||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | 分子: MolmilJmol/JSmol |
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 6bcx.cif.gz | 2.6 MB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb6bcx.ent.gz | 表示 | PDB形式 | |
PDBx/mmJSON形式 | 6bcx.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
文書・要旨 | 6bcx_validation.pdf.gz | 1.1 MB | 表示 | wwPDB検証レポート |
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文書・詳細版 | 6bcx_full_validation.pdf.gz | 1.1 MB | 表示 | |
XML形式データ | 6bcx_validation.xml.gz | 158.8 KB | 表示 | |
CIF形式データ | 6bcx_validation.cif.gz | 253.1 KB | 表示 | |
アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/bc/6bcx ftp://data.pdbj.org/pub/pdb/validation_reports/bc/6bcx | HTTPS FTP |
-関連構造データ
関連構造データ | 7087MC 7086C 5wbhC 5wbiC 5wbjC 5wbkC 5wblC 5wbuC 5wbyC 6bcuC 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 |
-リンク
-集合体
登録構造単位 |
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1 |
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-要素
-タンパク質 , 4種, 8分子 ABDEWYXZ
#1: タンパク質 | 分子量: 287399.125 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: MTOR, FRAP, FRAP1, FRAP2, RAFT1, RAPT1 / 発現宿主: Homo sapiens (ヒト) 参照: UniProt: P42345, non-specific serine/threonine protein kinase #2: タンパク質 | 分子量: 35910.090 Da / 分子数: 2 / Fragment: mLST8 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: MLST8, GBL, LST8 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: Q9BVC4 #3: タンパク質 | 分子量: 150197.000 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: RPTOR, KIAA1303, RAPTOR / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: Q8N122 #4: タンパク質 | 分子量: 12951.344 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: EIF4EBP1 / 発現宿主: Homo sapiens (ヒト) / 参照: UniProt: Q13541 |
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-非ポリマー , 2種, 6分子
#5: 化合物 | #6: 化合物 | ChemComp-MG / |
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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: Dimer of two mTOR-mLST8-RAPTOR-4EBP1 complexes. / タイプ: COMPLEX / Entity ID: #1-#4 / 由来: RECOMBINANT |
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分子量 | 実験値: NO |
由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Homo sapiens (ヒト) |
緩衝液 | pH: 8 |
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
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: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELD |
撮影 | 電子線照射量: 56 e/Å2 フィルム・検出器のモデル: GATAN K2 SUMMIT (4k x 4k) |
-解析
ソフトウェア | 名称: REFMAC / バージョン: 5.8.0158 / 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 AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
対称性 | 点対称性: C2 (2回回転対称) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 3.23 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 580768 / 対称性のタイプ: POINT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
原子モデル構築 | プロトコル: AB INITIO MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
精密化 | 解像度: 3.23→3.23 Å / Cor.coef. Fo:Fc: 0.859 / SU B: 23.164 / SU ML: 0.172 / ESU R: 0.272 立体化学のターゲット値: MAXIMUM LIKELIHOOD WITH PHASES 詳細: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
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溶媒の処理 | イオンプローブ半径: 0.8 Å / 減衰半径: 0.8 Å / VDWプローブ半径: 1 Å / 溶媒モデル: MASK | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
原子変位パラメータ | Biso mean: 31.329 Å2
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精密化ステップ | サイクル: 1 / 合計: 56580 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
拘束条件 |
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