Structural characterization of the interaction of mTOR with phosphatidic acid and a novel class of inhibitor: compelling evidence for a central role of the FRB domain in small molecule-mediated regulation of mTOR

摘要: The mammalian target of rapamycin (mTOR) is a large, multidomain protein kinase, which plays central role in the regulation cell growth and has recently emerged as an essential survival signals many types human cancer cells. Here, we report solution structures complexes formed between FKBP12-rapamycin binding (FRB) domain mTOR phosphatidic acid, important cellular activator FRB novel inhibitor (HTS-1). overall structure very similar to that seen ternary complex with FKBP12 immunosuppressive drug rapamycin; however, there are significant changes within rapamycin-binding site consequences for rational design. surface contains number distinctive features have previously escaped attention, including potential new regulatory on opposite face involved rapamycin, displays expected specific small molecule. interaction sites acid HTS-1 were found closely match responsible binding. In addition, determined FRB-phosphatidic FRB-HTS-1 revealed striking similarity conformations buried portions ligands backbone contact domain. Our findings further highlight importance molecule-mediated mTOR, demonstrate ability identify inhibitors bind tightly absence FKBP12, may be exploited design anticancer drugs.