Selective ATP-competitive inhibitors of TOR suppress rapamycin-insensitive function of TORC2 in Saccharomyces cerevisiae.
Selective ATP-competitive inhibitors of TOR suppress rapamycin-insensitive function of TORC2 in Saccharomyces cerevisiae.
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TOR 的选择性 ATP 竞争性抑制剂可抑制酿酒酵母中 TORC2 的雷帕霉素不敏感功能。
DOI：
10.1021/cb300058v
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发表时间：
2012
影响因子：
4
通讯作者：
Gray,NathanaelS
中科院分区：
文献类型：
--
作者：
Liu,Qingsong;Ren,Tao;Fresques,Tara;Oppliger,Wolfgang;Niles,BradJ;Hur,Wooyoung;Sabatini,DavidM;Hall,MichaelN;Powers,Ted;Gray,NathanaelS
雷帕霉素(TOR)的靶点是生长、存活和能量代谢的关键调节因子。变构TORC1抑制剂雷帕霉素已被广泛用于阐明TOR相关信号通路，但由于其不能抑制TORC2而受到限制。我们使用了一种无偏倚的细胞增殖实验，发现QL-IX-55是一种有效的酿酒酵母生长抑制因子。通过合理的设计和无偏的选择策略发现了TOR2的抗性等位基因，证明了QL-IX-55的功能靶点是TOR2的ATP结合位点。QL-IX-55能够有效地抑制TOR复合体1和2(TORC1和TORC2)，这一点通过生化IP激酶检测(IC50<；50 nM)和细胞检测对底物YPK1磷酸化的抑制来证明。与雷帕霉素相反，QL-IX-55能够抑制TORC2依赖的转录，这表明该化合物将成为剖析酵母中Tor2/TORC2相关信号通路的有力探针。
The target of rapamycin (TOR) is a critical regulator of growth, survival, and energy metabolism. The allosteric TORC1 inhibitor rapamycin has been used extensively to elucidate the TOR related signal pathway but is limited by its inability to inhibit TORC2. We used an unbiased cell proliferation assay of a kinase inhibitor library to discover QL-IX-55 as a potent inhibitor of S.cerevisiaegrowth. The functional target of QL-IX-55 is the ATP-binding site of TOR2 as evidenced by the discovery of resistant alleles of TOR2 through rational design and unbiased selection strategies. QL-IX-55 is capable of potently inhibiting both TOR complex 1 and 2 (TORC1 and TORC2) as demonstrated by biochemical IP kinase assays (IC50<50 nM) and cellular assays for inhibition of substrate YPK1 phosphorylation. In contrast to rapamycin, QL-IX-55 is capable of inhibiting TORC2-dependent transcription, which suggests that this compound will be a powerful probe to dissect the Tor2/TORC2-related signaling pathway in yeast.
影响因子：
7.3
作者：
Liu Q;Chang JW;Wang J;Kang SA;Thoreen CC;Markhard A;Hur W;Zhang J;Sim T;Sabatini DM;Gray NS
通讯作者：
Gray NS
影响因子：
3.7
作者：
Dinér P;Veide Vilg J;Kjellén J;Migdal I;Andersson T;Gebbia M;Giaever G;Nislow C;Hohmann S;Wysocki R;Tamás MJ;Grøtli M
通讯作者：
Grøtli M
代谢控制机制。雷帕霉素信号传导的靶标将氮质量与RTG1和RTG3转录因子的活性联系起来。
影响因子：
7.8
作者：
Komeili, A;Wedaman, K P;O'Shea, E K;Powers, T
通讯作者：
Powers, T