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mTOR kinase structure, mechanism and regulation

Haijuan Yang1, Derek G Rudge, Joseph D Koos

  • 1Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

Nature
|May 3, 2013
PubMed

Insights

The mammalian target of rapamycin (mTOR) kinase structure reveals an intrinsically active conformation. Its activity is regulated by restricted active site access, controlled by the FRB domain and an inhibitory helix.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • The mammalian target of rapamycin (mTOR) is a key regulator of cell growth, frequently dysregulated in cancer.
  • Understanding mTOR's structure and regulation is crucial for developing targeted cancer therapies.

Purpose of the Study:

  • To elucidate the co-crystal structures of a truncated mTOR-mLST8 complex.
  • To investigate the structural basis of mTOR activation and inhibition.

Main Methods:

  • Co-crystal structure determination of mTOR-mLST8 complex with ATP transition state mimic and inhibitors.
  • In vitro biochemical assays to study substrate access and inhibition mechanisms.

Main Results:

  • The mTOR kinase exhibits an intrinsically active conformation with a recessed active site.
  • The FKBP12-rapamycin-binding (FRB) domain acts as a gatekeeper, regulating substrate access.
  • Rapamycin-FKBP12 inhibits mTOR by blocking substrate recruitment and restricting active-site access.
  • mTOR-activating mutations affect the structural framework controlling active site access.

Conclusions:

  • mTOR's kinase activity is tightly regulated by restricted access to its active site.
  • The FRB domain plays a critical role in substrate recognition and mTOR regulation.
  • Structural insights provide a basis for understanding mTOR inhibitor potency and specificity.

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