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- PDB-5flc: Architecture of human mTOR Complex 1 - 5.9 Angstrom reconstruction -

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Basic information

Entry
Database: PDB / ID: 5flc
TitleArchitecture of human mTOR Complex 1 - 5.9 Angstrom reconstruction
Components
  • (SERINE/THREONINE-PROTEIN KINASE ...) x 3
  • FKBP
  • REGULATORY-ASSOCIATED PROTEIN OF MTOR
  • TARGET OF RAPAMYCIN COMPLEX SUBUNIT LST8
KeywordsTRANSFERASE / RAPAMYCIN / MTORC1
Function / homology
Function and homology information


positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process / 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 / 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 / regulation of membrane permeability / TORC2 complex ...positive regulation of SCF-dependent proteasomal ubiquitin-dependent catabolic process / 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 / 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 / regulation of membrane permeability / TORC2 complex / cellular response to leucine starvation / TFIIIC-class transcription factor complex binding / heart valve morphogenesis / negative regulation of lysosome organization / voluntary musculoskeletal movement / TORC1 complex / calcineurin-NFAT signaling cascade / positive regulation of transcription of nucleolar large rRNA by RNA polymerase I / RNA polymerase III type 3 promoter sequence-specific DNA binding / positive regulation of keratinocyte migration / regulation of osteoclast differentiation / MTOR signalling / energy reserve metabolic process / regulation of lysosome organization / cellular response to L-leucine / regulation of autophagosome assembly / Energy dependent regulation of mTOR by LKB1-AMPK / cellular response to nutrient / Amino acids regulate mTORC1 / cellular response to methionine / negative regulation of cell size / TORC2 signaling / cellular response to osmotic stress / cell projection organization / anoikis / inositol hexakisphosphate binding / cardiac muscle cell development / negative regulation of calcineurin-NFAT signaling cascade / positive regulation of ubiquitin-dependent protein catabolic process / regulation of myelination / negative regulation of protein localization to nucleus / positive regulation of transcription by RNA polymerase III / positive regulation of ruffle assembly / regulation of cell size / Macroautophagy / positive regulation of myotube differentiation / negative regulation of macroautophagy / Constitutive Signaling by AKT1 E17K in Cancer / germ cell development / positive regulation of actin filament polymerization / oligodendrocyte differentiation / TORC1 signaling / positive regulation of oligodendrocyte differentiation / behavioral response to pain / mTORC1-mediated signalling / TOR signaling / response to amino acid / positive regulation of translational initiation / CD28 dependent PI3K/Akt signaling / HSF1-dependent transactivation / regulation of macroautophagy / positive regulation of TOR signaling / 'de novo' pyrimidine nucleobase biosynthetic process / positive regulation of epithelial to mesenchymal transition / positive regulation of lipid biosynthetic process / vascular endothelial cell response to laminar fluid shear stress / heart morphogenesis / regulation of cellular response to heat / positive regulation of lamellipodium assembly / neuronal action potential / phagocytic vesicle / T cell costimulation / positive regulation of stress fiber assembly / cardiac muscle contraction / negative regulation of insulin receptor signaling pathway / endomembrane system / cytoskeleton organization / cellular response to nutrient levels / positive regulation of glycolytic process / cellular response to amino acid starvation / Regulation of PTEN gene transcription / cellular response to starvation / regulation of signal transduction by p53 class mediator / negative regulation of autophagy / VEGFR2 mediated vascular permeability / protein serine/threonine kinase activator activity / post-embryonic development / TP53 Regulates Metabolic Genes / positive regulation of translation / regulation of actin cytoskeleton organization / non-specific protein-tyrosine kinase / macroautophagy / cellular response to amino acid stimulus / non-membrane spanning protein tyrosine kinase activity / phosphoprotein binding / regulation of cell growth / regulation of circadian rhythm / response to nutrient levels / PML body / protein destabilization
Similarity search - Function
Target of rapamycin complex subunit LST8 / Domain of unknown function DUF3385, target of rapamycin protein / Serine/threonine-protein kinase mTOR domain / Domain of unknown function / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / Rapamycin binding domain / : ...Target of rapamycin complex subunit LST8 / Domain of unknown function DUF3385, target of rapamycin protein / Serine/threonine-protein kinase mTOR domain / Domain of unknown function / FKBP12-rapamycin binding domain / Serine/threonine-protein kinase TOR / FKBP12-rapamycin binding domain superfamily / FKBP12-rapamycin binding domain / Rapamycin binding domain / : / Serine/threonine-protein kinase ATR-like, HEAT repeats / : / FATC domain / PIK-related kinase, FAT / FAT domain / FATC / FATC domain / PIK-related kinase / FAT domain profile. / FATC domain profile. / Quinoprotein alcohol dehydrogenase-like superfamily / Phosphatidylinositol 3- and 4-kinases signature 1. / Phosphatidylinositol 3/4-kinase, conserved site / Phosphatidylinositol 3- and 4-kinases signature 2. / Phosphatidylinositol 3-/4-kinase, catalytic domain superfamily / Phosphoinositide 3-kinase, catalytic domain / Phosphatidylinositol 3- and 4-kinase / Phosphatidylinositol 3- and 4-kinases catalytic domain profile. / Phosphatidylinositol 3-/4-kinase, catalytic domain / Armadillo-like helical / Tetratricopeptide-like helical domain superfamily / WD domain, G-beta repeat / Armadillo-type fold / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase-like domain superfamily
Similarity search - Domain/homology
RAPAMYCIN IMMUNOSUPPRESSANT DRUG / Serine/threonine-protein kinase mTOR / Target of rapamycin complex subunit LST8
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
SPODOPTERA FRUGIPERDA (fall armyworm)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 5.9 Å
AuthorsAylett, C.H.S. / Sauer, E. / Imseng, S. / Boehringer, D. / Hall, M.N. / Ban, N. / Maier, T.
CitationJournal: Science / Year: 2016
Title: Architecture of human mTOR complex 1.
Authors: Christopher H S Aylett / Evelyn Sauer / Stefan Imseng / Daniel Boehringer / Michael N Hall / Nenad Ban / Timm Maier /
Abstract: Target of rapamycin (TOR), a conserved protein kinase and central controller of cell growth, functions in two structurally and functionally distinct complexes: TORC1 and TORC2. Dysregulation of ...Target of rapamycin (TOR), a conserved protein kinase and central controller of cell growth, functions in two structurally and functionally distinct complexes: TORC1 and TORC2. Dysregulation of mammalian TOR (mTOR) signaling is implicated in pathologies that include diabetes, cancer, and neurodegeneration. We resolved the architecture of human mTORC1 (mTOR with subunits Raptor and mLST8) bound to FK506 binding protein (FKBP)-rapamycin, by combining cryo-electron microscopy at 5.9 angstrom resolution with crystallographic studies of Chaetomium thermophilum Raptor at 4.3 angstrom resolution. The structure explains how FKBP-rapamycin and architectural elements of mTORC1 limit access to the recessed active site. Consistent with a role in substrate recognition and delivery, the conserved amino-terminal domain of Raptor is juxtaposed to the kinase active site.
History
DepositionOct 23, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 30, 2015Provider: repository / Type: Initial release
Revision 1.1Jan 13, 2016Group: Database references
Revision 1.2Aug 2, 2017Group: Data collection / Category: em_image_scans / em_software
Item: _em_software.fitting_id / _em_software.image_processing_id / _em_software.name
Revision 1.3Apr 24, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / pdbx_seq_map_depositor_info
Item: _entity_src_gen.pdbx_host_org_cell_line / _pdbx_seq_map_depositor_info.one_letter_code_mod
Revision 1.4May 8, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Movie
  • Deposited structure unit
  • Imaged by Jmol
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  • Superimposition on EM map
  • EMDB-3213
  • Imaged by UCSF Chimera
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Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
1: SERINE/THREONINE-PROTEIN KINASE MTOR
2: SERINE/THREONINE-PROTEIN KINASE MTOR
3: SERINE/THREONINE-PROTEIN KINASE MTOR
4: SERINE/THREONINE-PROTEIN KINASE MTOR
A: REGULATORY-ASSOCIATED PROTEIN OF MTOR
B: SERINE/THREONINE-PROTEIN KINASE MTOR
C: FKBP
D: TARGET OF RAPAMYCIN COMPLEX SUBUNIT LST8
E: REGULATORY-ASSOCIATED PROTEIN OF MTOR
F: SERINE/THREONINE-PROTEIN KINASE MTOR
G: FKBP
H: TARGET OF RAPAMYCIN COMPLEX SUBUNIT LST8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)702,02814
Polymers700,20012
Non-polymers1,8282
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA

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Components

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SERINE/THREONINE-PROTEIN KINASE ... , 3 types, 6 molecules 1324BF

#1: Protein SERINE/THREONINE-PROTEIN KINASE MTOR / FK506-BINDING PROTEIN 12-RAPAMYCIN COMPLEX-ASSOCIATED PROTEIN 1 / FKBP12-RAPAMYCIN COMPLEX- ...FK506-BINDING PROTEIN 12-RAPAMYCIN COMPLEX-ASSOCIATED PROTEIN 1 / FKBP12-RAPAMYCIN COMPLEX-ASSOCIATED PROTEIN / MAMMALIAN TARGET OF RAPAMYCIN / MTOR / MECHANISTIC TARGET OF RAPAMYCIN / RAPAMYCIN AND FKBP12 TARGET 1 / RAPAMYCIN TARGET PROTEIN 1


Mass: 52357.672 Da / Num. of mol.: 2 / Fragment: HORN DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: non-specific serine/threonine protein kinase
#2: Protein SERINE/THREONINE-PROTEIN KINASE MTOR / FK506-BINDING PROTEIN 12-RAPAMYCIN COMPLEX-ASSOCIATED PROTEIN 1 / FKBP12-RAPAMYCIN COMPLEX- ...FK506-BINDING PROTEIN 12-RAPAMYCIN COMPLEX-ASSOCIATED PROTEIN 1 / FKBP12-RAPAMYCIN COMPLEX-ASSOCIATED PROTEIN / MAMMALIAN TARGET OF RAPAMYCIN / MTOR / MECHANISTIC TARGET OF RAPAMYCIN / RAPAMYCIN AND FKBP12 TARGET 1 / RAPAMYCIN TARGET PROTEIN 1


Mass: 31081.197 Da / Num. of mol.: 2 / Fragment: BRIDGE DOMAIN
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: non-specific serine/threonine protein kinase
#4: Protein SERINE/THREONINE-PROTEIN KINASE MTOR / FK506-BINDING PROTEIN 12-RAPAMYCIN COMPLEX-ASSOCIATED PROTEIN 1 / FKBP12-RAPAMYCIN COMPLEX- ...FK506-BINDING PROTEIN 12-RAPAMYCIN COMPLEX-ASSOCIATED PROTEIN 1 / FKBP12-RAPAMYCIN COMPLEX-ASSOCIATED PROTEIN / MAMMALIAN TARGET OF RAPAMYCIN / MTOR / MECHANISTIC TARGET OF RAPAMYCIN / RAPAMYCIN A ND FKBP12 TARGET 1 / RAPAMYCIN TARGET PROTEIN 1


Mass: 134036.641 Da / Num. of mol.: 2 / Fragment: FAT AND PIKK DOMAINS
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P42345, non-specific serine/threonine protein kinase

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Protein , 3 types, 6 molecules AECGDH

#3: Protein REGULATORY-ASSOCIATED PROTEIN OF MTOR / RAPTOR / P150 TARGET OF RAPAMYCIN (TOR)-SCAFFOLD PROTEIN


Mass: 87589.977 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
#5: Protein FKBP


Mass: 9124.238 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) SPODOPTERA FRUGIPERDA (fall armyworm)
#6: Protein TARGET OF RAPAMYCIN COMPLEX SUBUNIT LST8 / TORC SUBUNIT LST8 / G PROTEIN BETA SUBUNIT-LIKE / GABLE / PROTEIN GBETAL / MAMMALIAN LETHAL WITH ...TORC SUBUNIT LST8 / G PROTEIN BETA SUBUNIT-LIKE / GABLE / PROTEIN GBETAL / MAMMALIAN LETHAL WITH SEC13 PROTEIN 8 / MLST8


Mass: 35910.090 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: Q9BVC4

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Non-polymers , 1 types, 2 molecules

#7: Chemical ChemComp-RAP / RAPAMYCIN IMMUNOSUPPRESSANT DRUG


Mass: 914.172 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C51H79NO13 / Comment: immunosuppressant, antibiotic*YM

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: HUMAN MTOR COMPLEX 1 / Type: COMPLEX
Buffer solutionName: 100 MM NACL, 10 MM NABICINE, 1 MM TCEP / pH: 8 / Details: 100 MM NACL, 10 MM NABICINE, 1 MM TCEP
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: CARBON
VitrificationInstrument: FEI VITROBOT MARK I / Cryogen name: ETHANE
Details: VITRIFICATION 1 -- CRYOGEN- ETHANE, HUMIDITY- 100, TEMPERATURE- 120, INSTRUMENT- FEI VITROBOT MARK I, METHOD- 4 SECOND BLOTTING,

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS / Date: May 5, 2015
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 59000 X / Calibrated magnification: 100719 X / Nominal defocus max: 4000 nm / Nominal defocus min: 1900 nm / Cs: 2.7 mm
Specimen holderTemperature: 100 K
Image recordingElectron dose: 25 e/Å2 / Film or detector model: FEI FALCON II (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1CTFFIND3CTF correction
2UCSF Chimeramodel fitting
3RELION1.33D reconstruction
CTF correctionDetails: EACH IMAGE
SymmetryPoint symmetry: C2 (2 fold cyclic)
3D reconstructionMethod: MAXIMUM A POSTERIORI PROJECTION MATCHING / Resolution: 5.9 Å / Num. of particles: 309792 / Nominal pixel size: 1.39 Å / Actual pixel size: 1.39 Å
Details: THE UNK CHAINS (A, E, C, G, 1-4) CORRESPONDING TO RAPTOR (A,E), SF FKBP AND RAPAMYCIN (C,G) AND THE N-TERMINAL HEAT REPEATS OF MTOR (1-4), HAVE BEEN NUMBERED FROM 100 AT EACH BREAK TO ...Details: THE UNK CHAINS (A, E, C, G, 1-4) CORRESPONDING TO RAPTOR (A,E), SF FKBP AND RAPAMYCIN (C,G) AND THE N-TERMINAL HEAT REPEATS OF MTOR (1-4), HAVE BEEN NUMBERED FROM 100 AT EACH BREAK TO INDICATE LACK OF SEQUENCE - DENSITY CERTAINTY. CHAINS 1-4 CORRESPOND TO THE N-TERMINAL HEAT REPEAT DOMAINS OF MTOR. WE PROPOSE A TOPOLOGY IN THE CORRESPONDING PAPER (1-2-B AND 3-4-F), BUT GIVEN THE FACT THAT THEIR TOPOLOGY CANNOT BE ASSIGNED DEFINITIVELY THEY ARE REPRESENTED AS A SEPARATE CHAIN FOR EACH DOMAIN. THE FITTING OF CRYSTAL STRUCTURES FOR THE MTOR FAT AND PIKK DOMAINS, MLST8, RAPTOR AND FKBP ALLOWS THEIR DENSITY TO BE ASSIGNED DEFINITIVELY, AND THEIR CHAINS ARE THEREFORE LETTERED. SUBMISSION BASED ON EXPERIMENTAL DATA FROM EMDB EMD-3213. (DEPOSITION ID: 13912).
Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Target criteria: FSC / Details: METHOD--RIGID BODY
RefinementHighest resolution: 5.9 Å
Refinement stepCycle: LAST / Highest resolution: 5.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms47398 0 130 0 47528

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