6月21日,，Structure雜志報道了RNA適配子選擇性抑制G蛋白偶聯(lián)受體激酶2（GRK2）的分子機(jī)制,。這可為基于GRK2的心血管系統(tǒng)的新藥研發(fā)提供重要的參考。
心血管系統(tǒng)穩(wěn)態(tài)的維持,，部分是通過G蛋白偶聯(lián)受體激酶2（GRK2）磷酸化活化的七次螺旋受體,，使之快速脫敏來實(shí)現(xiàn)的。
然而,，在慢性心臟衰竭過程中GRK2上調(diào),。這使研究者認(rèn)為它促進(jìn)了病情的惡化。研究者已經(jīng)確定GRK2與RNA適配子結(jié)合復(fù)合物的晶體結(jié)構(gòu),。RNA適配子的結(jié)合可有力且選擇性地抑制激酶活性,。
抑制機(jī)制的關(guān)鍵是將RNA適配子的一個腺嘌呤核苷酸定位于GRK2的ATP結(jié)合口袋以及RNA適配子與GRK2激酶結(jié)構(gòu)域αF-αG環(huán)狀區(qū)域間的相互作用。終端的適配子莖狀機(jī)構(gòu)對RNA施加的限制也對這種抑制做出了貢獻(xiàn),。這些研究結(jié)果揭示了高親和力適配子如何選擇性地捕獲一種新的蛋白激酶的構(gòu)象狀態(tài),。（生物谷bioon.com）
doi:10.1016/j.cell.2011.10.017
PMC:
PMID:
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.
