Cutting edge:: IL-1 receptor-associated kinase 4 structures reveal novel features and multiple conformations
Cutting edge:: IL-1 receptor-associated kinase 4 structures reveal novel features and multiple conformations
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DOI：
10.4049/jimmunol.178.5.2641
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发表时间：
2007-03-01
影响因子：
4.4
通讯作者：
Browner, Michelle F.
中科院分区：
文献类型：
--
作者：
Kuglstatter, Andreas;Villasenor, Armando G.;Browner, Michelle F.
IL-1 R相关激酶（IRAK）4在先天性和适应性免疫中起着核心作用，并且是IL-1/TLR信号传导的关键组分。我们已经确定了人IRAK 4激酶结构域的载脂蛋白和配体结合形式的晶体结构。这些结构揭示了为设计选择性IRAK 4抑制剂提供机会的几个特征。IRAK 4激酶结构域的N-末端叶由于在延伸的N-末端螺旋后插入环而在结构上是独特的。看门人残基是酪氨酸，这是IRAK家族的独特特征。IRAK 4结构还提供了对其活性调节的见解。在载脂蛋白结构中，两种构象共存，不同的是两个激酶叶的相对方向和螺旋C的位置。在ATP类似物的存在下，仅观察到一种构象，表明这是活性构象。
IL-1R-associated kinase (IRAK)4 plays a central role in innate and adaptive immunity, and is a crucial component in IL-1/TLR signaling. We have determined the crystal structures of the apo and ligand-bound forms of human IRAK4 kinase domain. These structures reveal several features that provide opportunities for the design of selective IRAK4 inhibitors. The N-terminal lobe of the IRAK4 kinase domain is structurally distinctive due to a loop insertion after an extended N-terminal helix. The gatekeeper residue is a tyrosine, a unique feature of the IRAK family. The IRAK4 structures also provide insights into the regulation of its activity. In the apo structure, two conformations coexist, differing in the relative orientation of the two kinase lobes and the position of helix C In the presence of an ATP analog only one conformation is observed, indicating that this is the active conformation.