Nature：两种药物实现大脑特异的 mTOR 抑制 - 知乎
作者报告了一种策略，通过使用脑渗透性mTOR抑制剂RapaLink-1和脑渗透性FKBP12配体RapaBlock，实现对哺乳动物雷帕霉素（mTOR）的抑制，同时在其他地方疏导mTOR活性。
mTOR抑制剂的研究进展 - 知乎 - 知乎专栏
第三代mTOR抑制剂RapaLink-1(75)是将雷帕霉素和mTOR激酶抑制剂MLN018整合到同一个分子上而获得的，其通过结合FKBP12的FRB结构域作用于mTOR，同时连接的小分子抑制剂MLN018作用于mTOR激酶结构域。
FKBPs and the Akt/mTOR pathway - PMC - PubMed Central (PMC)
FKBP12 and 12.6 have been repeatedly reported to fine-tune the responsiveness of receptor tyrosine kinases (e.g., TGFR or EGFR) 20, 21 or of calcium channels (ryanodine receptors, TRP channels), 22 often by acting as an adaptor protein to inhibit their basal activity. FKBP12 was also suggested to promote the depalmitoylation of H-ras. 23
Rapamycin recruits SIRT2 for FKBP12 deacetylation during mTOR …
2021年11月19日 · FK506-binding protein 12 (FKBP12) inhibits mTOR kinase activity via direct association. The FKBP12-mTOR association can be strengthened by the immunosuppressant rapamycin, but the underlying mechanism remains elusive. We show here that the FKBP12-mTOR association is tightly regulated by an acetylation–deacetylation cycle.
Removal of FKBP12 enhances mTOR-Raptor interactions, LTP ... - PubMed
2008年12月10日 · FK506-binding protein 12 (FKBP12) binds the immunosuppressant drugs FK506 and rapamycin and regulates several signaling pathways, including mammalian target of rapamycin (mTOR) signaling. We determined whether the brain-specific disruption of the FKBP12 gene in mice altered mTOR signaling, synaptic …
Removal of FKBP12 Enhances mTOR-Raptor Interactions
2008年12月10日 · We examined the effects of the genetic deletion of the FKBP12 protein on mTOR signaling, synaptic plasticity, and memory. In biochemical experiments we found that deletion of FKBP12 was associated with enhanced mTOR phosphorylation, an increase in the interaction between mTOR and Raptor, and enhanced phosphorylation of the mTOR target S6K.
Brain-restricted mTOR inhibition with binary pharmacology
2022年9月14日 · Here we report a strategy to achieve inhibition of mammalian target of rapamycin (mTOR) while sparing mTOR activity elsewhere through the use of the brain-permeable mTOR inhibitor RapaLink-1...
Rapamycin-inspired macrocycles with new target specificity
2018年12月10日 · The FKBP12–rapamycin complex can then bind to mTOR and block its kinase activity towards downstream substrates such as p70S6K and 4E-BP, while the FKBP12-FK506 complex interacts with...
mTOR kinase structure, mechanism and regulation | Nature
2013年5月1日 · Rapamycin–FKBP12 inhibits the kinase by directly blocking substrate recruitment and by further restricting active-site access. The structures also reveal active-site residues and...
Characterization of the FKBP·Rapamycin·FRB Ternary Complex
2005年3月9日 · These studies suggest that rapamycin's ability to bind to FRB, and by extension to mTOR, in the absence of FKBP is of little consequence under physiological conditions. Furthermore, protein−protein interactions at the FKBP12−FRB interface play a role in the stability of the ternary complex.