mTOR kinase structure, mechanism and regulation

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.