Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog
Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog
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DOI：
10.1182/blood-2005-02-0707
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发表时间：
2005-08-01
期刊：
影响因子：
20.3
通讯作者：
Eck, MJ
中科院分区：
文献类型：
--
作者：
Boggon, TJ;Li, YQ;Eck, MJ
Jak（Janus激酶）家族非受体酪氨酸激酶是细胞因子信号传导的中心介质。Jak激酶表现出不同的细胞因子受体结合特征，因此具有不同的信号。Jak 3的表达仅限于免疫系统，在免疫系统中，它在从含有常见γ链γ c的细胞因子受体的信号转导中起关键作用。不能通过γ c发出信号的患者表现为严重联合免疫缺陷（SCID）。Jak 3突变导致SCID的发现使其成为开发淋巴细胞特异性免疫抑制剂的靶点。在这里，我们提出了晶体结构的Jak 3激酶结构域与星形孢菌素类似物AFN 941的复合物。激酶结构域处于活性构象，两个活化环酪氨酸残基都磷酸化。活化环中pTyr 981上的磷酸基团部分由调节C-螺旋中的精氨酸残基协调，表明C-螺旋的活性位置由活化环的磷酸化诱导的直接机制。这种直接偶联以前在酪氨酸激酶中没有观察到，并且可能是Jak激酶所特有的。晶体结构提供了Jak 3活性位点的详细视图，并将促进计算和结构导向的方法来开发Jak 3特异性抑制剂。
Jak (Janus kinase) family nonreceptor tyrosine kinases are central mediators of cytokine signaling. The Jak kinases exhibit distinct cytokine receptor association profiles and so transduce different signals. Jak3 expression is limited to the immune system, where it plays a key role in signal transduction from cytolkine receptors containing the common gammachain, gamma c. Patients unable to signal via gamma c present with severe combined immunodeficiency (SCID). The finding that Jak3 mutations result in SCID has made it a target for development of lymphocytespecific immunosuppressants. Here, we present the crystal structure of the Jak3 kinase domain in complex with staurosporine analog AFN941. The kinase domain is in the active conformation, with both activation loop tyrosine residues phosphorylated. The phosphate group on pTyr981 in the activation loop is in part coordinated by an arginine residue in the regulatory C-helix, suggesting a direct mechanism by which the active position of the C-helix is induced by phosphorylation of the activation loop. Such a direct coupling has not been previously observed in tyrosine kinases and may be unique to Jak kinases. The crystal structure provides a detailed view of the Jak3 active site and will facilitate computational and structure-directed approaches to development of Jak3-specific inhibitors.