The FRB Domain of mTOR: NMR Solution Structure and Inhibitor Design
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- 作者：Marilisa Leone ; Kevin J. Crowell ; Jinhua Chen ; Dawoon Jung ; Gary G. Chiang ; Sina Sareth ; Robert T. Abraham ; Maurizio Pellecchia
- 刊名：Biochemistry
- 出版年：2006
- 出版时间：August 29, 2006
- 年：2006
- 卷：45
- 期：34
- 页码：10294 - 10302
- 全文大小：666K
- 年卷期：v.45,no.34(August 29, 2006)
- ISSN：1520-4995
文摘
The mammalian target of rapamycin (mTOR) is a protein that is intricately involved in signalingpathways controlling cell growth. Rapamycin is a natural product that binds and inhibits mTOR functionby interacting with its FKBP-rapamycin-binding (FRB) domain. Here we report on the NMR solutionstructure of FRB and on further studies aimed at the identification and characterization of novel ligandsthat target the rapamycin binding pocket. The biological activity of the ligands, and that of rapamycin inthe absence of FKBP12, was investigated by assaying the kinase activity of mTOR. While we found thatrapamycin binds the FRB domain and inhibits the kinase activity of mTOR even in the absence of FKBP12(in the low micromolar range), our most potent ligands bind to FRB with similar binding affinity butinhibit the kinase activity of mTOR at much higher concentrations. However, we have also identified onelow-affinity compound that is also capable of inhibiting mTOR. Hence, we have identified compoundsthat can directly mimic rapamycin or can dissociate the FRB binding from the inhibition of the catalyticactivity of mTOR. As such, these ligands could be useful in deciphering the complex regulation of mTORin the cell and in validating the FRB domain as a possible target for the development of novel therapeuticcompounds.