FKBP12
Rapamycin's docking protein. Rapamycin first binds FKBP12; only the FKBP12-rapamycin pair can grab mTOR. This is why rapamycin is an 'allosteric' (indirect) inhibitor - it works through a chaperone, not by blocking the active site.
The protein rapamycin must borrow. The 'docking protein' rapamycin needs to work. Rapamycin first grabs onto this protein, and only that combined pair can then latch onto and block mTOR - which is why rapamycin is called an indirect ('allosteric') inhibitor rather than one that blocks mTOR's active site directly.
FKBP1A. Rapamycin has essentially no activity against mTOR without it, which is why FKBP12 expression sets rapalog sensitivity.
TL;DR. FKBP12 appears in 3 curated studies in Oliver's mTOR Atlas: 3 at the molecular level (cells, biochemistry, structure). No study in people is recorded for it in the Atlas yet. It has 2 interactions in the curated pathway model.
In the pathway model
| Interaction | Mechanism | Evidence | Studies |
|---|---|---|---|
| FKBP12 binds mTORC1 mechanism: binding · this link in full · on the map table | Only when it carries rapamycin does FKBP12 dock on mTORC1; the pair then blocks some, but not all, of what mTORC1 does. FKBP12 on its own does nothing to mTORC1. Only when it is carrying rapamycin, FKBP12 docks on the FRB domain next to mTOR's active site. The FKBP12-rapamycin complex, not FKBP12 alone, is what blocks access for some substrates but not all; FKBP12 without the drug does not inhibit mTORC1. The inhibitory arrow is drawn from rapamycin (RAPA-MTORC1). Only when it is carrying rapamycin, FKBP12 docks on the FRB domain next to mTOR's active site. The FKBP12-rapamycin complex, not FKBP12 alone, is what blocks access for some substrates but not all; FKBP12 without the drug does not inhibit mTORC1. The inhibitory arrow is drawn from rapamycin (RAPA-MTORC1). Holds under: Biochemical and structural work on rat and bovine brain extracts, rodent and T cells, and a cryo-EM structure of human mTORC1. It defines how the drug-bound complex docks. FKBP12 alone does not inhibit mTORC1, and effects in whole animals are carried by the rapamycin edges, not this one. plausible in people, not shown directly · settled in the literature | M | SAB1994, SAB1995, CHU1992, BRO1994, AYL2015 |
| Rapamycin binds FKBP12 mechanism: binding · this link in full · on the map table | Rapamycin doesn't work alone – it first has to team up with a helper protein called FKBP12. Rapamycin is not an ordinary inhibitor: it first binds the small protein FKBP12, and only the two-part complex is the real drug. Rapamycin is not an ordinary inhibitor: it first binds the small protein FKBP12, and only the two-part complex is the real drug. Holds under: X-ray crystallography and in vitro work on bovine, rat and mouse material (CHO1996, BRO1994, SAB1995). Describes drug binding in purified systems; it says nothing about dose or effect in patients. plausible in people, not shown directly · settled in the literature | M | CHO1996, BRO1994, SAB1995 |
Evidence at a glance
| Evidence | What it means | Studies |
|---|---|---|
| M | Molecular — cells, biochemistry, structure | 3 |
No direct human evidence in the Atlas for this entity yet — everything below rests on animal or molecular work.
Studies
| Year | Evidence | Study |
|---|---|---|
| 2015 | M | Architecture of human mTOR complex 1 AYL2015 Cryo-EM architecture of human mTORC1 reveals its dimeric organization and active site access. |
| 2013 | M | mTOR kinase structure, mechanism and regulation YAN2013 Solved the crystal structure of the mTOR kinase itself. Revealed why the active site is so hard to reach - it sits in a deep recess guarded by the FRB domain, which acts as a 'gatekeeper' letting substrates in. This structure explains at the atomic level exactly how FKBP12-rapamycin blocks access, and why activating cancer mutations cluster where they do. |
| 1996 | M | Structure of the FKBP12-rapamycin complex interacting with the binding domain of human FRAP CHO1996 The crystal structure that showed HOW rapamycin works at the atomic level: one rapamycin molecule glues two proteins together - FKBP12 and mTOR's FRB domain - by plugging into two hydrophobic pockets at once. A textbook example of a small molecule acting as 'molecular glue' to force protein dimerization. |
Related entities
Thank you. Your answer was counted anonymously.