Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent.
Modulation of activation-loop phosphorylation by JAK inhibitors is binding mode dependent.
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DOI：
10.1158/2159-8290.cd-11-0324
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发表时间：
2012-06
期刊：
影响因子：
28.2
通讯作者：
Radimerski T
中科院分区：
文献类型：
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作者：
Andraos R;Qian Z;Bonenfant D;Rubert J;Vangrevelinghe E;Scheufler C;Marque F;Régnier CH;De Pover A;Ryckelynck H;Bhagwat N;Koppikar P;Goel A;Wyder L;Tavares G;Baffert F;Pissot-Soldermann C;Manley PW;Gaul C;Voshol H;Levine RL;Sellers WR;Hofmann F;Radimerski T
JAK抑制剂正在开发用于治疗类风湿性关节炎、牛皮癣、骨髓增生性肿瘤和白血病。这些药物中的大多数靶向ATP结合口袋并稳定JAK激酶的活性构象。这种I型结合模式导致JAK激活环磷酸化增加，尽管激酶功能被阻断。在这里，我们报告说，稳定的非活性状态，通过II型抑制作用以相反的方式，导致激活环磷酸化的损失。我们使用X射线晶体学来证实结合模式，并首次报告了JAK2激酶结构域处于非活性构象的晶体结构。重要的是，JAK激酶诱导的激活环磷酸化需要受体相互作用，以及完整的激酶和假激酶结构域。因此，根据JAK抑制剂稳定的相应构象，可能会或可能不会引起激活环的过度磷酸化。
JAK inhibitors are being developed for the treatment of rheumatoid arthritis, psoriasis, myeloproliferative neoplasms and leukemias. Most of these drugs target the ATP-binding pocket and stabilize the active conformation of the JAK kinases. This type-I binding mode leads to an increase in JAK activation-loop phosphorylation, despite blockade of kinase function. Here we report that stabilizing the inactive state via type-II inhibition acts in the opposite manner, leading to a loss of activation-loop phosphorylation. We used X-ray crystallography to corroborate the binding mode and report for the first time the crystal structure of the JAK2 kinase domain in an inactive conformation. Importantly, JAK inhibitor-induced activation-loop phosphorylation requires receptor interaction, as well as intact kinase and pseudokinase domains. Hence, depending on the respective conformation stabilized by a JAK inhibitor, hyperphosphorylation of the activation-loop may or may not be elicited.