Structure of the human mTOR complex I and its implications for rapamycin inhibition
What this study shows
The authors purified intact, active human mTORC1 and solved its shape by cryo-electron microscopy at about 26 angstrom resolution. The complex is an obligate dimer with a rhomboid outline and a central cavity, held together by interlocking contacts between mTOR and Raptor; antibody labelling placed mLST8 at the outer 'feet' and PRAS40 next to Raptor. Exposing purified mTORC1 to FKBP12-rapamycin first added a bound density in about 10% of particles, then broke the complex apart, with virtually no intact particles left after one hour, while the ATP-competitive inhibitor Torin1 left it intact. In matching kinase assays, FKBP12-rapamycin blocked S6K1 phosphorylation quickly but 4E-BP1 phosphorylation only after at least 60 minutes, and Raptor-free mTOR still phosphorylated S6K1 (rapamycin-sensitively) but not 4E-BP1. The authors proposed that rapamycin inhibits the two substrates by different mechanisms. Boundary: Purified protein and low-resolution EM; the authors note that in cells rapamycin neither fully blocks 4E-BP1 phosphorylation nor dismantles mTORC1, so the disassembly model is an in vitro result.
At a glance
| Evidence type | M Molecular — cells, biochemistry, structure Marked M because it is molecular or in-vitro work (model: Human mTORC1 purified from HEK-293T cells stably expressing FLAG-raptor; negative-stain and cryo-EM (26 A); antibody labelling; in vitro kinase assays on S6K1 and 4E-BP1 with FKBP12-rapamycin or Torin1) rather than a whole-organism health-outcome study. That is often exactly where causal biology gets established -- the code says which system the finding was shown in, and nothing about how good the work is. |
| Study type | 5 - Mechanistic / In Vitro |
| Model system | Human mTORC1 purified from HEK-293T cells stably expressing FLAG-raptor; negative-stain and cryo-EM (26 A); antibody labelling; in vitro kinase assays on S6K1 and 4E-BP1 with FKBP12-rapamycin or Torin1 |
| Journal | Molecular Cell |
| Year | 2010 |
| Peer reviewed | Yes |
| Record last updated | 2026-10-01 |
| Source | DOI 10.1016/j.molcel.2010.05.017 · PMID 20542007 · Free full text (PMC2887672) |
Extracted findings
These fields were extracted from the paper with AI assistance and have not been checked against the source. Read them as a pointer into the paper, not as curated claims; where they disagree with the curated summary above, the curated summary stands.
| Intervention | FKBP12-rapamycin or Torin1 on purified mTORC1; Raptor-free mTOR preparations |
| Target | mTORC1 (mTOR-Raptor dimer) |
| Model | Human (protein purified from HEK-293T cells) |
| Effect | FKBP12-rapamycin bound mTORC1 and, over time, disassembled it; S6K1 phosphorylation fell quickly, 4E-BP1 phosphorylation only after prolonged exposure |
In the Atlas
Related topics
Links in the pathway map
- Supports FKBP12 binds mTORC1
- Supports Rapamycin inhibits mTORC1
More studies on this topic
- Architecture of human mTOR complex 1 (2015)
- Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP (1996)
- mTOR kinase structure, mechanism and regulation (2013)
- Tor forms a dimer through an N-terminal helical solenoid with a complex topology (2016)
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