6月21日，Structure杂志报道了RNA适配子选择性抑制G蛋白偶联受体激酶2（GRK2）的分子机制。这可为基于GRK2的心血管系统的新药研发提供重要的参考。
心血管系统稳态的维持，部分是通过G蛋白偶联受体激酶2（GRK2）磷酸化活化的七次螺旋受体，使之快速脱敏来实现的。
然而，在慢性心脏衰竭过程中GRK2上调。这使研究者认为它促进了病情的恶化。研究者已经确定GRK2与RNA适配子结合复合物的晶体结构。RNA适配子的结合可有力且选择性地抑制激酶活性。
抑制机制的关键是将RNA适配子的一个腺嘌呤核苷酸定位于GRK2的ATP结合口袋以及RNA适配子与GRK2激酶结构域αF-αG环状区域间的相互作用。终端的适配子茎状机构对RNA施加的限制也对这种抑制做出了贡献。这些研究结果揭示了高亲和力适配子如何选择性地捕获一种新的蛋白激酶的构象状态。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
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Molecular Mechanism for Inhibition of G Protein-Coupled Receptor Kinase 2 by a Selective RNA Aptamer
Valerie M. Tesmer, Sabine Lennarz, Günter Mayer, John J.G. Tesmer
Cardiovascular homeostasis is maintained in part by the rapid desensitization of activated heptahelical receptors that have been phosphorylated by G protein-coupled receptor kinase 2 (GRK2). However, during chronic heart failure GRK2 is upregulated and believed to contribute to disease progression. We have determined crystallographic structures of GRK2 bound to an RNA aptamer that potently and selectively inhibits kinase activity. Key to the mechanism of inhibition is the positioning of an adenine nucleotide into the ATP-binding pocket and interactions with the basic αF-αG loop region of the GRK2 kinase domain. Constraints imposed on the RNA by the terminal stem of the aptamer also play a role. These results highlight how a high-affinity aptamer can be used to selectively trap a novel conformational state of a protein kinase.
