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Structure paper

TitleThe 3.2-Å resolution structure of human mTORC2.
Journal, issue, pagesSci Adv, Vol. 6, Issue 45, Year 2020
Publish dateNov 6, 2020
AuthorsAlain Scaiola / Francesca Mangia / Stefan Imseng / Daniel Boehringer / Karolin Berneiser / Mitsugu Shimobayashi / Edward Stuttfeld / Michael N Hall / Nenad Ban / Timm Maier /
PubMed AbstractThe 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 ...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.
External linksSci Adv / PubMed:33158864 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 8.5 Å
Structure data

EMDB-11488, PDB-6zwm:
cryo-EM structure of human mTOR complex 2, overall refinement
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-11489:
cryo-EM structure of human mTOR complex 2 in absence of ATP-gamma-S
Method: EM (single particle) / Resolution: 4.1 Å

EMDB-11490:
Human mTOR complex 2 with additional density close to the mLST8
Method: EM (single particle) / Resolution: 5.2 Å

EMDB-11491:
Human mTOR complex 2 with additional density close to the mLST8
Method: EM (single particle) / Resolution: 8.5 Å

EMDB-11492, PDB-6zwo:
cryo-EM structure of human mTOR complex 2, focused on one half
Method: EM (single particle) / Resolution: 3.0 Å

Chemicals

ChemComp-AGS:
PHOSPHOTHIOPHOSPHORIC ACID-ADENYLATE ESTER / ATP-gamma-S, energy-carrying molecule analogue*YM

ChemComp-IHP:
INOSITOL HEXAKISPHOSPHATE / Phytic acid

ChemComp-ZN:
Unknown entry

ChemComp-ACE:
ACETYL GROUP / Acetyl group

Source
  • homo sapiens (human)
KeywordsTRANSFERASE / mTOR / Kinase / Complex / Inositol

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