rapamycinbinding

Rapamycin binding refers to the interaction of the macrolide rapamycin with intracellular receptor proteins to form a complex that modulates cellular signaling. In most biological contexts, rapamycin first binds to the immunophilin FKBP12 (FK506-binding protein 12), producing a high-affinity binary complex. This complex then binds to the FRB (FKBP12-rapamycin-binding) domain of the kinase mTOR, yielding an allosteric inhibition of mTOR Complex 1 (mTORC1) activity. The interaction is well characterized as a protein–protein–small-molecule assembly rather than a simple competitive ligand binding event.

Binding affinity and specificity: Rapamycin binds FKBP12 with sub-nanomolar to low-nanomolar affinity, enabling efficient formation of the FKBP12–rapamycin complex. The resulting ternary complex interacts with the FRB domain of mTOR, inhibiting phosphorylation of downstream targets such as S6K1 and 4E-BP1. This mechanism is distinct from ATP-competitive inhibitors of the kinase and accounts for the immunosuppressive and antiproliferative effects observed in cells.

Structural basis: Structural studies reveal that the FKBP12–rapamycin complex docks into the FRB region of mTOR, with key contacts stabilizing the inhibitory conformation. The binding is sensitive to changes in the FRB domain and can be influenced by rapalogs and mutations.

Measurement and relevance: Binding interactions are routinely measured by techniques such as isothermal titration calorimetry and surface plasmon resonance, among others. Understanding rapamycin binding is central to therapeutic use in transplantation, oncology, and aging research, as well as to the design of rapalog inhibitors with altered binding properties.