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Publication Abstract from PubMed

The immunosuppressant and anti-cancer drug rapamycin works by inducing inhibitory protein complexes with the kinase mTOR, an important regulator of growth and proliferation. The obligatory accessory partner of rapamycin is believed to be FKBP12. Here we show that rapamycin complexes of larger FKBP protein family members can tightly bind to mTOR and potently inhibit its kinase activity. Co-crystal structures with FKBP51 and FKBP52 reveal the modified molecular binding mode of these alternative ternary complexes in detail. In cellular model systems, FKBP12 can be functionally replaced by larger FKBPs. When rapamycin dosage is limiting, mTOR inhibition of S6K phosphorylation can be enhanced by FKBP51 overexpression in mammalian cells, whereas FKBP12 is dispensable. FKBP51 could also enable the rapamycin-induced hyperphosphorylation of Akt, which depended on higher FKBP levels compared to rapamycin-induced inhibition of S6K phosphorylation. These insights provide a mechanistic rationale for a preferential mTOR inhibition in specific cells or tissues types by engaging specific FKBP homologs.

Large FK506-binding Proteins Shape the Pharmacology of Rapamycin.,Marz AM, Fabian AK, Kozany C, Bracher A, Hausch F Mol Cell Biol. 2013 Jan 28. PMID:23358420^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.