Flexibility and charge asymmetry in the activation loop of Src tyrosine kinases.
Flexibility and charge asymmetry in the activation loop of Src tyrosine kinases.
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DOI：
10.1002/prot.22153
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发表时间：
2009-02-01
影响因子：
2.9
通讯作者：
Roux, Benoit
中科院分区：
文献类型：
--
作者：
Banavali, Nilesh K.;Roux, Benoit
Src激酶的调节活性对细胞生长至关重要。Src激酶可通过位于催化结构域中央激活环中的一个酪氨酸的反式磷酸化而被激活。然而，由于在Src激酶的下调X射线结构中未观察到该酪氨酸所需的暴露情况，激活环的瞬时部分打开似乎对这类过程是必要的。伞形采样分子动力学模拟被用于表征Src激酶Hck中激活环亲水部分打开的自由能景观。该环更倾向于一种部分打开的构象，其中Tyr416的可及性增加，但仍部分被遮蔽。在Tyr416附近序列中带电残基的不对称分布有助于遮蔽，并且在Src家族成员中是保守的。涉及保守残基Glu310与Arg385或Arg409之间静电相互作用交换的构象平衡影响激活环的打开。基于这些观察结果，提出了一种未磷酸化的Tyr416进入外部催化位点的机制。
Regulated activity of Src kinases is critical for cell growth. Src kinases can be activated by trans-phosphorylation of a tyrosine located in the central activation loop of the catalytic domain. However, because the required exposure of this tyrosine is not observed in the down-regulated X-ray structures of Src kinases, transient partial opening of the activation loop appears to be necessary for such processes. Umbrella sampling molecular dynamics simulations are used to characterize the free energy landscape of opening of the hydrophilic part of the activation loop in the Src kinase Hck. The loop prefers a partially open conformation where Tyr416 has increased accessibility, but remains partly shielded. An asymmetric distribution of the charged residues in the sequence near Tyr416, which contributes to shielding, is found to be conserved in Src family members. A conformational equilibrium involving exchange of electrostatic interactions between the conserved residues Glu310 and Arg385 or Arg409 affects activation loop opening. A mechanism for access of unphosphorylated Tyr416 into an external catalytic site is suggested based on these observations.
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影响因子：
2.9
作者：
Banavali, Nilesh K.;Roux, Benoit
通讯作者：
Roux, Benoit
影响因子：
2.7
作者：
Burchat, A;Borhani, DW;Stachlewitz, RF
通讯作者：
Stachlewitz, RF
影响因子：
11.4
作者：
Hubbard, SR
通讯作者：
Hubbard, SR
影响因子：
3
作者：
BROOKS, BR;BRUCCOLERI, RE;KARPLUS, M
通讯作者：
KARPLUS, M
影响因子：
4.4
作者：
FELLER, SE;ZHANG, YH;BROOKS, BR
通讯作者：
BROOKS, BR