Möbitz Henrik
Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland.
Biochim Biophys Acta. 2015 Oct;1854(10 Pt B):1555-66. doi: 10.1016/j.bbapap.2015.03.009. Epub 2015 Apr 1.
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-αC or the DFG-motif is governed by the interaction between helix-αC and the DFG motif. In particular, the conformation of the DFG-motif is tightly correlated with the propensity of helix-αC displacement. Our analysis reveals detailed mechanisms for the displacement of helix-αC 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.
由于蛋白激酶与人类疾病相关，它们是一类重要的治疗靶点。构象是理解功能活性、抑制作用和序列如何关联的关键概念。我们基于通用残基命名法从蛋白质数据库中组装并注释哺乳动物结构激酶组。我们确定了DFG模体中甘氨酸周围的一个扭转角，其尖锐的分布轮廓对应于三种重叠构象。这使得能够定义一小部分簇，其分布显示出对活性构象的偏好。一个共同的基本原理将活性状态和非活性状态联系起来：活性构象的稳定以及通过αC螺旋或DFG模体的位移导致的失活受αC螺旋与DFG模体之间的相互作用支配。特别是，DFG模体的构象与αC螺旋位移的倾向紧密相关。我们的分析揭示了αC螺旋和DFG位移的详细机制，并增进了我们对单个残基作用的理解。通过汇集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。本文是名为《蛋白激酶抑制剂》的特刊的一部分。
