Survey of solution dynamics in Src kinase reveals allosteric cross talk between the ligand binding and regulatory sites.
Survey of solution dynamics in Src kinase reveals allosteric cross talk between the ligand binding and regulatory sites.
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DOI：
10.1038/s41467-017-02240-6
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发表时间：
2017-12-18
影响因子：
16.6
通讯作者：
Seeliger MA
中科院分区：
文献类型：
--
作者：
Tong M;Pelton JG;Gill ML;Zhang W;Picart F;Seeliger MA
蛋白酪氨酸激酶的催化结构域可以响应于调节输入而在活性和非活性构象之间相互转换。我们最近证明，Src激酶的特点是一个变构网络，夫妇底物结合位点。然而，对整个激酶结构域传播的构象和动态变化的程度仍然知之甚少。在这里，我们通过NMR监测构象选择性抑制剂对激酶骨架动力学的影响。我们发现，抑制剂结合和激活环自磷酸化诱导整个激酶的动态变化。我们确定了一个高度保守的氨基酸，Gly 449，这是必要的Src激活。最后，我们首次展示了SH 3-SH 2结构域如何在全长蛋白质的背景下扰动激酶结构域的动态。我们提供的Src激酶，导致相对稳定的活性或非活性构象和底物亲和力的调制的远程通信的实验支持。Src是一种典型的信号非受体蛋白酪氨酸激酶，在不同的构象之间相互转换。在这里，作者使用激酶抑制剂达沙替尼的变体来定义Src激酶的三种特定构象状态，并深入了解构象特异性抑制剂对Src动力学的影响。
The catalytic domain of protein tyrosine kinases can interconvert between active and inactive conformations in response to regulatory inputs. We recently demonstrated that Src kinase features an allosteric network that couples substrate-binding sites. However, the extent of conformational and dynamic changes that are propagated throughout the kinase domain remains poorly understood. Here, we monitor by NMR the effect of conformationally selective inhibitors on kinase backbone dynamics. We find that inhibitor binding and activation loop autophosphorylation induces dynamic changes across the entire kinase. We identify a highly conserved amino acid, Gly449, that is necessary for Src activation. Finally, we show for the first time how the SH3–SH2 domains perturb the dynamics of the kinase domain in the context of the full length protein. We provide experimental support for long-range communication in Src kinase that leads to the relative stabilization of active or inactive conformations and modulation of substrate affinity. Src is a prototypical signaling non-receptor protein tyrosine kinase that interconverts between distinct conformations. Here the authors use variants of the kinase-inhibitor dasatinib to define three specific conformational states of the Src kinase and shed insight on the effect of conformation-specific inhibitors on Src dynamics.
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