Target of rapamycin (TOR), a conserved protein kinase and the central controller of cell growth, functions in two structurally distinct complexes, TORC1 and TORC2, which perform different, albeit related, functions within the signaling pathways of the eukaryotic cell. Dysregulation of mammalian TOR (mTOR) signaling is implicated in pathologies that include diabetes, cancer, and neurodegeneration, while the immunosuppressant macrolide rapamycin remains a front-line treatment of choice for tens of thousands of organ transplant and coronary stent recipients worldwide.

We resolved the architecture of human mTORC bound to FKBP–rapamycin to a secondary structural level by combining cryo-electron microscopy at 5.9 Å resolution with crystallographic studies of Chaetomium thermophilum Raptor at 4.3 Å resolution. Our structure explains how FKBP-rapamycin and architectural elements of mTORC1 limit access to the recessed active site of the kinase domain. Consistent with its established role in substrate recognition and delivery, the conserved amino-terminal domain of Raptor was found to be juxtaposed to the active site, allowing us to propose a mechanism for its action in recruiting mTORC1 substrates.