6BCU

Cryo-EM structure of the activated RHEB-mTORC1 refined to 3.4 angstrom

This is a non-PDB format compatible entry.

Summary for 6BCU

• Entry DOI: 10.2210/pdb6bcu/pdb
• Related: 6BCX
• EMDB information: 7086
• Descriptor: Serine/threonine-protein kinase mTOR,Serine/threonine-protein kinase mTOR, Target of rapamycin complex subunit LST8, Regulatory-associated protein of mTOR,Regulatory-associated protein of mTOR, ... (8 entities in total)
• Functional Keywords: pikk, transferase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 10
• Total formula weight: 1016877.32

Authors

Pavletich, N.P.,Yang, H. (deposition date: 2017-10-20, release date: 2017-12-20, Last modification date: 2024-03-13)

Primary citation

Yang, H.,Jiang, X.,Li, B.,Yang, H.J.,Miller, M.,Yang, A.,Dhar, A.,Pavletich, N.P.
Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40.
Nature, 552:368-373, 2017

PubMed Abstract: The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 ångström cryo-electron microscopy structure of mTORC1 and the 3.4 ångström structure of activated RHEB-mTORC1. RHEB binds to mTOR distally from the kinase active site, yet causes a global conformational change that allosterically realigns active-site residues, accelerating catalysis. Cancer-associated hyperactivating mutations map to structural elements that maintain the inactive state, and we provide biochemical evidence that they mimic RHEB relieving auto-inhibition. We also present crystal structures of RAPTOR-TOS motif complexes that define the determinants of TOS recognition, of an mTOR FKBP12-rapamycin-binding (FRB) domain-substrate complex that establishes a second substrate-recruitment mechanism, and of a truncated mTOR-PRAS40 complex that reveals PRAS40 inhibits both substrate-recruitment sites. These findings help explain how mTORC1 selects its substrates, how its kinase activity is controlled, and how it is activated by cancer-associated mutations.

PubMed: 29236692
DOI: 10.1038/nature25023

Experimental method

ELECTRON MICROSCOPY (3.8 Å)