Department of Pharmaceutical Chemistry, School of Pharmacy, The University of Kansas, Lawrence, Kansas, United States of America.
PLoS Comput Biol. 2011 Oct;7(10):e1002179. doi: 10.1371/journal.pcbi.1002179. Epub 2011 Oct 6.
The emerging structural information about allosteric kinase complexes and the growing number of allosteric inhibitors call for a systematic strategy to delineate and classify mechanisms of allosteric regulation and long-range communication that control kinase activity. In this work, we have investigated mechanistic aspects of long-range communications in ABL and EGFR kinases based on the results of multiscale simulations of regulatory complexes and computational modeling of signal propagation in proteins. These approaches have been systematically employed to elucidate organizing molecular principles of allosteric signaling in the ABL and EGFR multi-domain regulatory complexes and analyze allosteric signatures of the gate-keeper cancer mutations. We have presented evidence that mechanisms of allosteric activation may have universally evolved in the ABL and EGFR regulatory complexes as a product of a functional cross-talk between the organizing αF-helix and conformationally adaptive αI-helix and αC-helix. These structural elements form a dynamic network of efficiently communicated clusters that may control the long-range interdomain coupling and allosteric activation. The results of this study have unveiled a unifying effect of the gate-keeper cancer mutations as catalysts of kinase activation, leading to the enhanced long-range communication among allosterically coupled segments and stabilization of the active kinase form. The results of this study can reconcile recent experimental studies of allosteric inhibition and long-range cooperativity between binding sites in protein kinases. The presented study offers a novel molecular insight into mechanistic aspects of allosteric kinase signaling and provides a quantitative picture of activation mechanisms in protein kinases at the atomic level.
新兴的变构激酶复合物结构信息和越来越多的变构抑制剂要求有一个系统的策略来描绘和分类控制激酶活性的变构调节和远程通讯的机制。在这项工作中，我们根据调节复合物的多尺度模拟和蛋白质中信号传递的计算建模的结果，研究了 ABL 和 EGFR 激酶中远程通讯的机制方面。这些方法已被系统地用于阐明 ABL 和 EGFR 多结构域调节复合物中变构信号的组织分子原理，并分析看门突变的变构特征。我们已经提出证据表明，变构激活机制可能在 ABL 和 EGFR 调节复合物中普遍进化，作为组织 αF-螺旋和构象适应性 αI-螺旋和 αC-螺旋之间功能交叉对话的产物。这些结构元素形成了一个有效的通讯簇的动态网络，它可以控制远程结构域间的偶联和变构激活。这项研究的结果揭示了看门突变作为激酶激活的催化剂的统一作用，导致变构偶联片段之间的增强的远程通讯和活性激酶形式的稳定。这项研究的结果可以调和最近关于蛋白激酶中变构抑制和结合位点之间远程协同作用的实验研究。所提出的研究为变构激酶信号的机制方面提供了新的分子见解，并在原子水平上提供了蛋白激酶激活机制的定量描述。
