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- PDB-9zbj: Cryo-EM structure of human apo mTORC2 -

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Basic information

Entry
Database: PDB / ID: 9zbj
TitleCryo-EM structure of human apo mTORC2
Components
  • Rapamycin-insensitive companion of mTOR
  • Serine/threonine-protein kinase mTOR
  • Target of rapamycin complex 2 subunit MAPKAP1
  • Target of rapamycin complex subunit LST8
KeywordsTRANSFERASE / cellular growth control
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 phosphatidylinositol 3-kinase/protein kinase B signal transduction / regulation of membrane permeability ...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 phosphatidylinositol 3-kinase/protein kinase B signal transduction / 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 / regulation of cellular response to oxidative stress / 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 / phosphatidic acid binding / negative regulation of Ras protein signal transduction / cellular response to methionine / embryo development ending in birth or egg hatching / phosphatidylinositol-3,4-bisphosphate binding / negative regulation of cell size / TORC2 signaling / cellular response to osmotic stress / phosphatidylinositol-3,5-bisphosphate binding / 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 / regulation of establishment of cell polarity / positive regulation of myotube differentiation / Macroautophagy / lipid biosynthetic process / negative regulation of macroautophagy / Constitutive Signaling by AKT1 E17K in Cancer / germ cell development / positive regulation of actin filament polymerization / oligodendrocyte differentiation / phosphatidylinositol-3,4,5-trisphosphate binding / 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 / enzyme-substrate adaptor activity / '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 / phosphatidylinositol-4,5-bisphosphate binding / positive regulation of endothelial cell proliferation / negative regulation of insulin receptor signaling pathway / endomembrane system / cytoskeleton organization / substantia nigra development / cellular response to nutrient levels / positive regulation of glycolytic process / cellular response to amino acid starvation / Regulation of PTEN gene transcription / regulation of signal transduction by p53 class mediator / cellular response to starvation / negative regulation of autophagy / VEGFR2 mediated vascular permeability / protein serine/threonine kinase activator activity
Similarity search - Function
Rapamycin-insensitive companion of mTOR, phosphorylation-site / Rapamycin-insensitive companion of mTOR, phosphorylation-site / Rapamycin-insensitive companion of mTOR, phosphorylation-site / Rapamycin-insensitive companion of mTOR, N-terminal domain / Pianissimo family / Rapamycin-insensitive companion of mTOR, middle domain / Rapamycin-insensitive companion of mTOR, domain 5 / Rapamycin-insensitive companion of mTOR, domain 4 / Rapamycin-insensitive companion of mTOR RasGEF_N domain / Rapamycin-insensitive companion of mTOR, N-term ...Rapamycin-insensitive companion of mTOR, phosphorylation-site / Rapamycin-insensitive companion of mTOR, phosphorylation-site / Rapamycin-insensitive companion of mTOR, phosphorylation-site / Rapamycin-insensitive companion of mTOR, N-terminal domain / Pianissimo family / Rapamycin-insensitive companion of mTOR, middle domain / Rapamycin-insensitive companion of mTOR, domain 5 / Rapamycin-insensitive companion of mTOR, domain 4 / Rapamycin-insensitive companion of mTOR RasGEF_N domain / Rapamycin-insensitive companion of mTOR, N-term / Rapamycin-insensitive companion of mTOR, middle domain / Rapamycin-insensitive companion of mTOR, domain 5 / Rapamycin-insensitive companion of mTOR RasGEF_N domain / Rapamycin-insensitive companion of mTOR, middle domain / Rapamycin-insensitive companion of mTOR, N-term / Rapamycin-insensitive companion of mTOR, domain 5 / : / SIN1 Ras-binding domain / Sin1, N-terminal / Stress-activated map kinase interacting protein 1 (SIN1) / TORC2 component Sin1/Avo1 / SAPK-interacting protein 1, Pleckstrin-homology domain / Sin1, middle CRIM domain / SAPK-interacting protein 1 (Sin1), middle CRIM domain / SAPK-interacting protein 1 (Sin1), Pleckstrin-homology / 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 / PH-like domain superfamily / 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
Serine/threonine-protein kinase mTOR / Rapamycin-insensitive companion of mTOR / Target of rapamycin complex 2 subunit MAPKAP1 / Target of rapamycin complex subunit LST8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsWranik, M. / Lee, J.M. / Rogala, K.B.
Funding support United States, Germany, 6items
OrganizationGrant numberCountry
National Institutes of Health/National Cancer Institute (NIH/NCI)K99/R00 CA255926 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)R35 GM150935 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)P30 CA124435 United States
Other privateShmunis Family Innovation Award United States
Other privateBridging Excellence Fellowship Germany
Other private United States
CitationJournal: Science / Year: 2026
Title: Structural basis for the recruitment and selective phosphorylation of Akt by mTORC2.
Authors: Martin S Taylor / Maggie Chen / Matthew Hancock / Maximilian Wranik / Bryant D Miller / Timothy R O'Meara / Brad A Palanski / Scott B Ficarro / Brian J Groendyke / Yufei Xiang / Kazuma T ...Authors: Martin S Taylor / Maggie Chen / Matthew Hancock / Maximilian Wranik / Bryant D Miller / Timothy R O'Meara / Brad A Palanski / Scott B Ficarro / Brian J Groendyke / Yufei Xiang / Kazuma T Kondo / Karen Y Linde-Garelli / Michelle J Lee / Dibyendu Mondal / Daniel Freund / Samantha Congreve / Kaay Matas / Maximiliaan Hennink / Kera Xibinaku / Max L Valenstein / Trevor van Eeuwen / Jarrod A Marto / Andrej Sali / Yi Shi / Nathanael S Gray / David M Sabatini / Nam Chu / Kacper B Rogala / Philip A Cole /
Abstract: The mechanistic target of rapamycin (mTOR) protein kinase forms two multiprotein complexes, mTORC1 and mTORC2, that function in distinct signaling pathways. mTORC1 is regulated by nutrients, and ...The mechanistic target of rapamycin (mTOR) protein kinase forms two multiprotein complexes, mTORC1 and mTORC2, that function in distinct signaling pathways. mTORC1 is regulated by nutrients, and mTORC2 is a central node in phosphoinositide-3 kinase (PI3K) and small guanosine triphosphate Ras signaling networks commonly deregulated in cancer and diabetes. Although mTOR phosphorylates many substrates in vitro, in cells, mTORC1 and mTORC2 have high specificity: mTORC2 phosphorylates the protein kinases Akt and PKC, but not closely related kinases that are mTORC1 substrates. To understand how mTORC2 recognizes substrates, we created semisynthetic probes to trap the mTORC2 :: Akt complex and determine its structure. Whereas most protein kinases recognize amino acids adjacent to the phosphorylation site, local sequence contributes little to substrate recognition by mTORC2. Instead, the specificity determinants were secondary and tertiary structural elements of Akt that bound the mTORC2 component mSin1 distal to the mTOR active site and were conserved among at least 18 related substrates. These results reveal how mTORC2 recognizes its canonical substrates and may enable the design of mTORC2-specific inhibitors.
History
DepositionNov 20, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 15, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Serine/threonine-protein kinase mTOR
B: Target of rapamycin complex subunit LST8
C: Rapamycin-insensitive companion of mTOR
D: Target of rapamycin complex 2 subunit MAPKAP1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)507,5795
Polymers507,5144
Non-polymers651
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Noncrystallographic symmetry (NCS)NCS oper:
IDCodeMatrixVector
1given(1), (1), (1)
2generate(-1), (-1), (1)334.213, 334.213

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Components

#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 / Tyrosine-protein kinase mTOR


Mass: 266891.906 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MTOR, FRAP, FRAP1, FRAP2, RAFT1, RAPT1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P42345, non-specific serine/threonine protein kinase, non-specific protein-tyrosine kinase
#2: 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: 35053.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MLST8, GBL, LST8 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BVC4
#3: Protein Rapamycin-insensitive companion of mTOR / AVO3 homolog / hAVO3


Mass: 188647.688 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: RICTOR, KIAA1999 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q6R327
#4: Protein Target of rapamycin complex 2 subunit MAPKAP1 / TORC2 subunit MAPKAP1 / Mitogen-activated protein kinase 2-associated protein 1 / Stress-activated ...TORC2 subunit MAPKAP1 / Mitogen-activated protein kinase 2-associated protein 1 / Stress-activated map kinase-interacting protein 1 / SAPK-interacting protein 1 / mSIN1


Mass: 16921.117 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MAPKAP1, MIP1, SIN1 / Cell line (production host): Sf9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BPZ7
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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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: mTORC2 apo / Type: COMPLEX / Entity ID: #1, #3-#4, #2 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm) / Cell: Sf9
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: 4D-STEM / Nominal defocus max: 2000 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm
Image recordingElectron dose: 62.2 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1Topaz2.6.4particle selection
2PHENIX1.21.1_5286model refinement
13cryoSPARC53D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 1049398 / Symmetry type: POINT
RefinementHighest resolution: 3.2 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00128645
ELECTRON MICROSCOPYf_angle_d0.39938881
ELECTRON MICROSCOPYf_dihedral_angle_d9.76610353
ELECTRON MICROSCOPYf_chiral_restr0.0364491
ELECTRON MICROSCOPYf_plane_restr0.0035002

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