title: The structural basis for mTOR function.
abstract: The phosphoinositide 3-kinase (PI3K) related protein kinases (PIKKs) are a family of protein kinases with a diverse range of vital cellular functions. Recent high-resolution crystal structures of the protein kinase mTOR suggest general architectural principles that are likely to be common to all of the PIKKs. Furthermore, the structures make clear the close relationship of the PIKKs to the PI3Ks. However, the structures also make clear the unique features of mTOR that enable its substrate specificity. The active site is deeply recessed and flanked by structural elements unique to the PIKKs, namely, the FRB domain, the LST8 binding element, and a C-terminal stretch of helices known as the FATC domain. The FRB has a conserved element in it that is part of a bipartite substrate recognition mechanism that is probably characteristic of all of the PIKKs. The FRB also binds the mTOR inhibitor rapamycin that has been referred to as an allosteric inhibitor, implying that this inhibitor is actually a competitive inhibitor of the protein substrate. This bipartite substrate-binding site also helps clarify how rapamycin can result in substrate-specific inhibition.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: domi@mrc-lmb.cam.ac.uk.
authors.forename: Domagoj
authors.initials: D
authors.lastname: Baretić
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK. Electronic address: rlw@mrc-lmb.cam.ac.uk.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Williams
mesh_terms: D002384:Catalysis; D020134:Catalytic Domain; D004789:Enzyme Activation; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human
keywords: 4E-BP1; PI3K; PIKK; Rapamycin; S6K1; mTOR