Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site
Structure of a NEMO/IKK-associating domain reveals architecture of the interaction site
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DOI：
10.1016/j.str.2008.02.012
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发表时间：
2008-05-01
期刊：
影响因子：
5.7
通讯作者：
Lugovskoy, Alexey
中科院分区：
文献类型：
--
作者：
Rushe, Mia;Silvian, Laura;Lugovskoy, Alexey
IKK复合物对I κ B的磷酸化靶向其降解并释放NF-κ B以转位到细胞核中，从而引发炎症反应、细胞增殖或细胞分化。IKK复合物由催化性IKK α/β激酶和调节蛋白NF-κ B必需调节剂（NEMO; IKK γ）组成。NEMO与未磷酸化的IKK激酶C末端结合并激活IKK复合物的催化活性。然而，关于NEMO/IKK相互作用的详细结构信息缺乏。在这项研究中，我们已经确定了NEMO和IKK激酶协会使用各种生物物理技术的最低要求，并解决了最小的NEMO/IKK激酶关联域的两个晶体结构。我们证明了NEMO核心结构域是一个二聚体，结合两个IKK片段，并确定了能量热点，可用于抑制IKK复合物的形成与治疗剂。
The phosphorylation Of I kappa B by the IKK complex targets it for degradation and releases NF-kappa B for translocation into the nucleus to initiate the inflammatory response, cell proliferation, or cell differentiation. The IKK complex is composed of the catalytic IKK alpha/beta kinases and a regulatory protein, NF-kappa B essential modulator (NEMO; IKK gamma). NEMO associates with the unphosphorylated IKK kinase C termini and activates the IKK complex's catalytic activity. However, detailed structural information about the NEMO/IKK interaction is lacking. In this study, we have identified the minimal requirements for NEMO and IKK kinase association using a variety of biophysical techniques and have solved two crystal structures of the minimal NEMO/IKK kinase associating domains. We demonstrate that the NEMO core domain is a dimer that binds two IKK fragments and identify energetic hot spots that can be exploited to inhibit IKK complex formation with a therapeutic agent.