6ZWM

cryo-EM structure of human mTOR complex 2, overall refinement


Experimental Data Snapshot

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.20 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

wwPDB Validation   3D Report Full Report


This is version 1.0 of the entry. See complete history


Literature

The 3.2- angstrom resolution structure of human mTORC2.

Scaiola, A.Mangia, F.Imseng, S.Boehringer, D.Berneiser, K.Shimobayashi, M.Stuttfeld, E.Hall, M.N.Ban, N.Maier, T.

(2020) Sci Adv 6

  • DOI: https://doi.org/10.1126/sciadv.abc1251
  • Primary Citation of Related Structures:  
    6ZWM, 6ZWO

  • PubMed Abstract: 

    The protein kinase mammalian target of rapamycin (mTOR) is the central regulator of cell growth. Aberrant mTOR signaling is linked to cancer, diabetes, and neurological disorders. mTOR exerts its functions in two distinct multiprotein complexes, mTORC1 and mTORC2. Here, we report a 3.2-Å resolution cryo-EM reconstruction of mTORC2. It reveals entangled folds of the defining Rictor and the substrate-binding SIN1 subunits, identifies the carboxyl-terminal domain of Rictor as the source of the rapamycin insensitivity of mTORC2, and resolves mechanisms for mTORC2 regulation by complex destabilization. Two previously uncharacterized small-molecule binding sites are visualized, an inositol hexakisphosphate (InsP6) pocket in mTOR and an mTORC2-specific nucleotide binding site in Rictor, which also forms a zinc finger. Structural and biochemical analyses suggest that InsP6 and nucleotide binding do not control mTORC2 activity directly but rather have roles in folding or ternary interactions. These insights provide a firm basis for studying mTORC2 signaling and for developing mTORC2-specific inhibitors.


  • Organizational Affiliation

    Institute for Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine/threonine-protein kinase mTOR
A, B
2,549Homo sapiensMutation(s): 0 
Gene Names: MTORFRAPFRAP1FRAP2RAFT1RAPT1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P42345 (Homo sapiens)
Explore P42345 
Go to UniProtKB:  P42345
PHAROS:  P42345
GTEx:  ENSG00000198793 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP42345
Sequence Annotations
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  • Reference Sequence
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Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Target of rapamycin complex subunit LST8
C, D
326Homo sapiensMutation(s): 0 
Gene Names: MLST8GBLLST8
UniProt & NIH Common Fund Data Resources
Find proteins for Q9BVC4 (Homo sapiens)
Explore Q9BVC4 
Go to UniProtKB:  Q9BVC4
PHAROS:  Q9BVC4
GTEx:  ENSG00000167965 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9BVC4
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  • Reference Sequence
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Entity ID: 3
MoleculeChains Sequence LengthOrganismDetailsImage
Rapamycin-insensitive companion of mTOR
E, F
1,708Homo sapiensMutation(s): 0 
Gene Names: RICTORKIAA1999
UniProt & NIH Common Fund Data Resources
Find proteins for Q6R327 (Homo sapiens)
Explore Q6R327 
Go to UniProtKB:  Q6R327
PHAROS:  Q6R327
GTEx:  ENSG00000164327 
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UniProt GroupQ6R327
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  • Reference Sequence
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Entity ID: 4
MoleculeChains Sequence LengthOrganismDetailsImage
Target of rapamycin complex 2 subunit MAPKAP1
G, H
522Homo sapiensMutation(s): 0 
Gene Names: MAPKAP1MIP1SIN1
UniProt & NIH Common Fund Data Resources
Find proteins for Q9BPZ7 (Homo sapiens)
Explore Q9BPZ7 
Go to UniProtKB:  Q9BPZ7
PHAROS:  Q9BPZ7
GTEx:  ENSG00000119487 
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UniProt GroupQ9BPZ7
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  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
IHP (Subject of Investigation/LOI)
Query on IHP

Download Ideal Coordinates CCD File 
J [auth A],
L [auth B]
INOSITOL HEXAKISPHOSPHATE
C6 H18 O24 P6
IMQLKJBTEOYOSI-GPIVLXJGSA-N
AGS (Subject of Investigation/LOI)
Query on AGS

Download Ideal Coordinates CCD File 
I [auth A],
K [auth B],
N [auth E],
P [auth F]
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER
C10 H16 N5 O12 P3 S
NLTUCYMLOPLUHL-KQYNXXCUSA-N
ZN
Query on ZN

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M [auth E],
O [auth F]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
ACE
Query on ACE

Download Ideal Coordinates CCD File 
Q [auth G],
R [auth H]
ACETYL GROUP
C2 H4 O
IKHGUXGNUITLKF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: ELECTRON MICROSCOPY
  • Resolution: 3.20 Å
  • Aggregation State: PARTICLE 
  • Reconstruction Method: SINGLE PARTICLE 

Structure Validation

View Full Validation Report



Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Swiss National Science FoundationSwitzerland179323
Swiss National Science FoundationSwitzerland177084
Swiss National Science Foundation138262

Revision History  (Full details and data files)

  • Version 1.0: 2020-11-18
    Type: Initial release