mTOR adopts an intrinsically active conformation, but substrate access is tightly controlled.
Major finding: mTOR adopts an intrinsically active conformation, but substrate access is tightly controlled.
Clinical relevance: Rapamycin binding reduces accessibility of substrates to the mTOR catalytic cleft.
Impact: The mTOR kinase structure provides insight into determinants of inhibitor potency and specificity.
mTOR, a key regulator of cell growth, is commonly activated in cancers and is an attractive drug target. Yang and colleagues report the crystal structure of the catalytic region of mTOR together with the mTOR complex subunit LST8 and an ATP analogue. The authors found that the mTOR kinase domain forms a canonical 2-lobe structure seen in many other protein kinases, except that the N-terminal and C-terminal lobes extend to form a deep catalytic cleft that is partially obstructed. Because the mTOR kinase intrinsically adopted an active conformation when bound to an ATP mimic in the absence of additional regulatory subunits, these structural features suggest that negative regulation of mTOR occurs through restriction of active site access. Consistent with this possibility, most cancer-associated activating mutations affect residues surrounding the catalytic cleft and are predicted to loosen the restrictions on active site accessibility. Furthermore, superposition of a rapamycin-containing structure onto the mTOR–LST8 structure showed that docking of rapamycin would almost completely obstruct the catalytic cleft. This finding suggests that rapamycin acts as a competitive inhibitor of mTOR substrate binding, not as an allosteric mTOR inhibitor as previously thought. ATP-competitive mTOR inhibitors, however, reach a pocket at the back of the catalytic cleft, with distinct cleft features determining mTOR specificity relative to class I phosphoinositide 3-kinases. Together, these structural findings have the potential to provide insight into normal and pathologic mTOR function and regulation as well as guide the development of more potent and specific mTOR inhibitors.
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