A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases
A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases
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DOI：
10.1016/j.molcel.2007.06.028
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发表时间：
2007-09-07
期刊：
影响因子：
16
通讯作者：
Mohammadi, Moosa
中科院分区：
文献类型：
--
作者：
Chen, Huaibin;Ma, Jinghong;Mohammadi, Moosa
受体酪氨酸激酶(RTK)的酪氨酸激酶域的激活突变会导致癌症和骨骼疾病。将未磷酸化和磷酸化的野生型FGFR2激动域与7个未磷酸化的致病突变体的晶体结构进行比较，发现所有FGFRs的激酶铰链区的三个残基介导了一种自我抑制的“分子刹车”。结构分析表明，许多其他RTK，包括PDGFRs、VEGFRs、KIT、CSF1 R、Flt3、TEK和TIE，也受到这种刹车的调节。致病突变通过直接或间接地解除刹车而激活FGFRs和其他RTK。
Activating mutations in the tyrosine kinase domain of receptor tyrosine kinases (RTKs) cause cancer and skeletal disorders. Comparison of the crystal structures of unphosphorylated and phosphorylated wild-type FGFR2 kinase domains with those of seven unphosphorylated pathogenic mutants reveals an autoinhibitory "molecular brake" mediated by a triad of residues in the kinase hinge region of all FGFRs. Structural analysis shows that many other RTKs, including PDGFRs, VEGFRs, KIT, CSF1 R, FLT3, TEK, and TIE, are also subject to regulation by this brake. Pathogenic mutations activate FGFRs and other RTKs by disengaging the brake either directly or indirectly.