Conformational dynamics of human protein kinase CK2α and its effect on function and inhibition
Conformational dynamics of human protein kinase CK2α and its effect on function and inhibition
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人蛋白激酶CK2α的构象动力学及其对功能和抑制的影响
DOI：
10.1002/prot.25444
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Stephan Irle and Florence Tama
中科院分区：
文献类型：
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作者：
Ashutosh Srivastava; Tsuyoshi Hirota; Stephan Irle and Florence Tama
酪蛋白激酶II （casein kinase II, CK2）是一种普遍表达且高度保守的蛋白激酶，具有组成活性。它磷酸化多种蛋白质，并在几个细胞过程中起关键作用。该酶的催化亚基（CK2α）显示出显著的柔韧性，这在迄今为止确定的许多晶体结构中得到了证明。本文通过多晶体结构分析和长时间尺度分子动力学模拟，探讨了CK2α的构象柔韧性。与在晶体结构系综中观察到的酶相比，酶在溶液中表现出相当高的柔韧性。在动力学过程中观察到位于活性位点附近的铰链区存在多种构象。我们进一步观察到，在这些多重构象中，最密集的构象状态在晶体结构集合中没有得到充分的代表。与“打开”铰链/αD态晶体结构相比，在这种状态下，催化棘被拆除的较少。未结合状态（Apo）和抑制剂（CX4945）结合状态的动力学比较显示抑制剂诱导的酶的整体动力学抑制。对于活性位点上方功能重要的富含甘氨酸的环尤其如此。总之，这项工作为CK2α在溶液中的动力学提供了新的见解，并将其与功能联系起来。该研究还解释了抑制剂对CK2α动力学的影响，为开发更好的抑制剂铺平了道路。
Protein kinase, casein kinase II (CK2), is ubiquitously expressed and highly conserved protein kinase that shows constitutive activity. It phosphorylates a diverse set of proteins and plays crucial role in several cellular processes. The catalytic subunit of this enzyme (CK2α) shows remarkable flexibility as evidenced in numerous crystal structures determined till now. Here, using analysis of multiple crystal structures and long timescale molecular dynamics simulations, we explore the conformational flexibility of CK2α. The enzyme shows considerably higher flexibility in the solution as compared to that observed in crystal structure ensemble. Multiple conformations of hinge region, located near the active site, were observed during the dynamics. We further observed that among these multiple conformations, the most populated conformational state was inadequately represented in the crystal structure ensemble. The catalytic spine, was found to be less dismantled in this state as compared to the “open” hinge/αD state crystal structures. The comparison of dynamics in unbound (Apo) state and inhibitor (CX4945) bound state exhibits inhibitor induced suppression in the overall dynamics of the enzyme. This is especially true for functionally important glycine‐rich loop above the active site. Together, this work gives novel insights into the dynamics of CK2α in solution and relates it to the function. This work also explains the effect of inhibitor on the dynamics of CK2α and paves way for development of better inhibitors.