Mechanistic target of rapamycin complex 1 – FKBP12-rapamycin binding domain (mTORC1-FRB) (mTORC1-FRB)

The Mechanistic target of rapamycin complex 1 (mTORC1) is a conserved serine/threonine kinase complex that functions as a central controller of cell growth, proliferation, and survival by sensing nutrient and energy levels (UniProt: P42345). The FKBP12-rapamycin binding (FRB) domain is a specific 100-amino acid structural motif within the mTOR protein that is essential for the inhibitory action of the natural product rapamycin and its synthetic derivatives, known as rapalogs (PubMed: 8662507). Upon entering the cell, rapamycin binds to the immunophilin FKBP12, and this binary complex then associates with the FRB domain of mTOR, effectively acting as a molecular wedge that blocks substrate recruitment and reduces kinase activity (PubMed: 24403073). Overactivation of the mTORC1 pathway is a hallmark of many human diseases, including various cancers and the genetic disorder tuberous sclerosis complex (TSC), where loss of inhibitory control leads to benign and malignant tumor formation (NIH: PMC3060444). Consequently, the FRB domain is a major therapeutic target for immunosuppression in transplantation and for the treatment of mTOR-driven malignancies and rare diseases like lymphangioleiomyomatosis (StatPearls: NBK537184).

Other names

FRB domain of mTORFKBP12-rapamycin binding domainmTOR FRB domainFKBP-rapamycin-associated protein domainRAST domain

Allosteric inhibition of the mTORC1 kinase complex via the formation of a ternary complex between the drug, FKBP12, and the FRB domain, which sterically hinders the access of substrates to the active site (PubMed: 24403073).