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Open data
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Basic information
Entry | Database: PDB / ID: 6bcx | ||||||
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Title | mTORC1 structure refined to 3.0 angstroms | ||||||
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![]() | TRANSFERASE / PIKK | ||||||
Function / homology | ![]() 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 / Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S / regulation of locomotor rhythm / positive regulation of wound healing, spreading of epidermal cells / eukaryotic initiation factor 4E binding / cellular response to leucine starvation ...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 / Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S / regulation of locomotor rhythm / positive regulation of wound healing, spreading of epidermal cells / eukaryotic initiation factor 4E binding / cellular response to leucine starvation / regulation of membrane permeability / TFIIIC-class transcription factor complex binding / heart valve morphogenesis / negative regulation of lysosome organization / RNA polymerase III type 3 promoter sequence-specific DNA binding / TORC2 complex / TORC1 complex / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / 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 / cellular response to L-leucine / MTOR signalling / Amino acids regulate mTORC1 / cellular response to nutrient / energy reserve metabolic process / Energy dependent regulation of mTOR by LKB1-AMPK / negative regulation of cell size / ruffle organization / protein serine/threonine kinase inhibitor activity / positive regulation of osteoclast differentiation / cellular response to osmotic stress / 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 / regulation of cell size / Macroautophagy / positive regulation of oligodendrocyte differentiation / negative regulation of macroautophagy / positive regulation of actin filament polymerization / lysosome organization / 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 / cellular response to nutrient levels / positive regulation of phosphoprotein phosphatase activity / social behavior / HSF1-dependent transactivation / 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 / positive regulation of lamellipodium assembly / positive regulation of epithelial to mesenchymal transition / positive regulation of lipid biosynthetic process / heart morphogenesis / cardiac muscle contraction / regulation of cellular response to heat / translation repressor activity / negative regulation of translational initiation / positive regulation of stress fiber assembly / 14-3-3 protein binding / positive regulation of endothelial cell proliferation / cytoskeleton organization / translation initiation factor binding / T cell costimulation / cellular response to amino acid starvation / phagocytic vesicle / positive regulation of glycolytic process / cellular response to starvation / negative regulation of autophagy / positive regulation of mitotic cell cycle / protein serine/threonine kinase activator activity / response to nutrient levels / response to nutrient / post-embryonic development / VEGFR2 mediated vascular permeability / positive regulation of peptidyl-threonine phosphorylation / regulation of signal transduction by p53 class mediator / Regulation of PTEN gene transcription / regulation of autophagy Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.23 Å | ||||||
![]() | Pavletich, N.P. / Yang, H. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Authors: Haijuan Yang / Xiaolu Jiang / Buren Li / Hyo J Yang / Meredith Miller / Angela Yang / Ankita Dhar / Nikola P Pavletich / ![]() Abstract: 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. | ||||||
History |
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Structure visualization
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 2.6 MB | Display | ![]() |
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PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.1 MB | Display | ![]() |
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Full document | ![]() | 1.1 MB | Display | |
Data in XML | ![]() | 158.8 KB | Display | |
Data in CIF | ![]() | 253.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7087MC ![]() 7086C ![]() 5wbhC ![]() 5wbiC ![]() 5wbjC ![]() 5wbkC ![]() 5wblC ![]() 5wbuC ![]() 5wbyC ![]() 6bcuC M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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Components
-Protein , 4 types, 8 molecules ABDEWYXZ
#1: Protein | Mass: 287399.125 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: P42345, non-specific serine/threonine protein kinase #2: Protein | Mass: 35910.090 Da / Num. of mol.: 2 / Fragment: mLST8 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #3: Protein | Mass: 150197.000 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() #4: Protein | Mass: 12951.344 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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-Non-polymers , 2 types, 6 molecules ![](data/chem/img/ATP.gif)
![](data/chem/img/MG.gif)
![](data/chem/img/MG.gif)
#5: Chemical | #6: Chemical | ChemComp-MG / |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Dimer of two mTOR-mLST8-RAPTOR-4EBP1 complexes. / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD |
Image recording | Electron dose: 56 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
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Processing
Software | Name: REFMAC / Version: 5.8.0158 / Classification: refinement | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Symmetry | Point symmetry: C2 (2 fold cyclic) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
3D reconstruction | Resolution: 3.23 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 580768 / Symmetry type: POINT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Atomic model building | Protocol: AB INITIO MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement | Resolution: 3.23→3.23 Å / Cor.coef. Fo:Fc: 0.859 / SU B: 23.164 / SU ML: 0.172 / ESU R: 0.272 Stereochemistry target values: MAXIMUM LIKELIHOOD WITH PHASES Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1 Å / Solvent model: MASK | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 31.329 Å2
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Refinement step | Cycle: 1 / Total: 56580 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refine LS restraints |
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