The ABC of protein kinase conformations
The ABC of protein kinase conformations
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DOI：
10.1016/j.bbapap.2015.03.009
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发表时间：
2015-10-01
影响因子：
3.2
通讯作者：
Moebitz, Henrik
中科院分区：
文献类型：
--
作者：
Moebitz, Henrik
由于它们参与人类疾病，蛋白激酶是重要的治疗靶标类别。构象是理解功能活性、抑制和序列如何联系的关键概念。我们组装和注释的哺乳动物结构激酶组蛋白质数据库的基础上，一个通用的残基命名。我们确定了一个扭转角周围的甘氨酸的DFG基序，其尖锐的分布轮廓对应于三个重叠的构象。这允许定义一小组簇，其分布显示出活性构象的偏差。一个共同的基本原理联系的活性和非活性状态：稳定的活性构象，以及通过置换螺旋-α C或DFG-基序的失活是由螺旋-α C和DFG基序之间的相互作用。特别地，DFG基序的构象与螺旋-α C置换的倾向紧密相关。我们的分析揭示了螺旋-α C和DFG的位移的详细机制，并提高了我们对单个残基的作用的理解。通过汇集来自整个结构激酶组的构象，可以在自由能分析中估计序列和外在因素的能量贡献。这篇文章是题为：蛋白激酶抑制剂的特刊的一部分。(C)2015 Elsevier B. V.版权所有。
Due to their involvement in human diseases, protein kinases are an important therapeutic target class. Conformation is a key concept for understanding how functional activity, inhibition and sequence are linked. We assemble and annotate the mammalian structural kinome from the Protein Data Bank on the basis of a universal residue nomenclature. We identify a torsion angle around the Gly of the DFG-motif whose sharp distribution profile corresponds to three eclipsed conformations. This allows the definition a small set of clusters whose distribution shows a bias for the active conformation. A common rationale links the active and inactive state: stabilization of the active conformation, as well as inactivation by displacement of helix-alpha C or the DFG-motif is governed by the interaction between helix-alpha C and the DFG motif. In particular, the conformation of the DFG-motif is tightly correlated with the propensity of helix-alpha C displacement. Our analysis reveals detailed mechanisms for the displacement of helix-alpha C and the DFG and improves our understanding of the role of individual residues. By pooling conformations from the whole structural kinome, the energetic contributions of sequence and extrinsic factors can be estimated in free energy analyses. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases. (C) 2015 Elsevier B.V. All rights reserved.