Department of Molecular and Cell Biology, University of Connecticut, Storrs, CT 06269, USA.
J Mol Biol. 2011 Nov 11;413(5):973-84. doi: 10.1016/j.jmb.2011.09.025. Epub 2011 Sep 28.
Protein kinase R (PKR) is an interferon-induced kinase that plays a pivotal role in the innate immunity pathway. PKR is activated to undergo autophosphorylation upon binding to double-stranded RNAs or RNAs that contain duplex regions. Activated PKR phosphorylates the α subunit of eukaryotic initiation factor 2, thereby inhibiting protein synthesis. PKR is also activated by heparin, a highly sulfated glycosaminoglycan. We have used biophysical methods to define the mechanism of PKR activation by heparin. Heparins as short as hexasaccharide bind strongly to PKR and activate autophosphorylation. In contrast to double-stranded RNA, heparin activates PKR by binding to the kinase domain. Analytical ultracentrifugation measurements support a thermodynamic linkage model where heparin binding allosterically enhances PKR dimerization, thereby activating the kinase. These results indicate that PKR can be activated by small molecules and represents a viable target for the development of novel antiviral agents.
蛋白激酶 R（PKR）是一种干扰素诱导的激酶，在先天免疫途径中发挥关键作用。PKR 结合双链 RNA 或含有双链区的 RNA 后被激活，发生自身磷酸化。活化的 PKR 磷酸化真核起始因子 2 的 α 亚基，从而抑制蛋白质合成。肝素是一种高度硫酸化的糖胺聚糖，也能激活 PKR。我们已经使用生物物理方法来定义肝素激活 PKR 的机制。短至六糖的肝素与 PKR 结合紧密，并激活自身磷酸化。与双链 RNA 不同，肝素通过与激酶结构域结合来激活 PKR。分析超速离心测量结果支持一个热力学连接模型，其中肝素结合变构增强 PKR 二聚化，从而激活激酶。这些结果表明，PKR 可以被小分子激活，是开发新型抗病毒药物的可行靶点。
