Zinc mediated dimer of human interferon-alpha(2b) revealed by X-ray crystallography
Zinc mediated dimer of human interferon-alpha(2b) revealed by X-ray crystallography
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DOI：
10.1016/s0969-2126(96)00152-9
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发表时间：
1996-12-15
期刊：
影响因子：
5.7
通讯作者：
Walter, MR
中科院分区：
文献类型：
--
作者：
Radhakrishnan, R;Walter, LJ;Walter, MR
背景：人α-干扰素家族在多种细胞类型上显示出广谱的抗病毒、抗增殖和免疫调节活性。干扰素-α的各种生物学活性是通过与细胞表面受体的特定相互作用传递给细胞的。尽管付出了相当大的努力，但由于蛋白质晶体的质量不适合进行结晶学研究，目前还没有这一家族成员的晶体结构的报道。到目前为止，干扰素-α的结构模型一直是基于小鼠干扰素-β的结构，这些模型可能是不准确的，因为干扰素-β的氨基酸序列与建议的受体结合部位的干扰素-α有很大的不同。结果：重组人干扰素-α(2b)(huIFN-α(2b))的晶体结构已确定为2.9埃分辨率，HuIFN-α(2b)以非共价二聚体形式存在于晶体中，并以一种新的方式结合。与其他结构表征的细胞因子不同，二聚体界面上的广泛相互作用是由锌离子(锌离子)介导的。Hu干扰素-α(2b)的整体折叠结构与干扰素-β的结构最为相似。Hu干扰素-α(2b)在AB环上有一个3(10)螺旋，通过二硫键连接到分子的核心。结论：Hu干扰素-α(2b)的结构为分析与>；15相关的I型干扰素分子提供了一个准确的模型，Hu干扰素-α(2b)在结构上与干扰素-β、白介素10和干扰素-γ有相当大的相似性，后者也与相关的2型细胞因子受体结合。通过这些结构比较和对突变对生物活性影响的大量研究，我们已经确定了似乎在受体激活中重要的蛋白质表面，这项研究也揭示了huIFN-α(2b)二聚体潜在的生物学意义。
Background: The human alpha-interferon (huIFN-alpha) family displays broad spectrum antiviral, antiproliferative and immunomodulatory activities on a variety of cell types. The diverse biological activities of the IFN-alpha's are conveyed to cells through specific interactions with cell-surface receptors. Despite considerable effort, no crystal structure of a member of this family has yet been reported, because the quality of the protein crystals have been unsuitable for crystallographic studies. Until now, structural models of the IFN-alpha's have been based on the structure of murine IFN-beta (mulFN-beta), These models are likely to be inaccurate, as the amino acid sequence of muIFN-beta differs significantly from the IFN-alpha's at proposed receptor-binding sites. Structural information on a huIFN-alpha subtype would provide an improved basis for modeling the structures of the entire IFN-alpha family.Results: The crystal structure of recombinant human interferon-alpha(2b) (huIFN-alpha(2b)) has been determined at 2.9 Angstrom resolution, HuIFN-alpha(2b) exists in the crystal as a noncovalent dimer, which associates in a novel manner. Unlike other structurally characterized cytokines, extensive interactions in the dimer interface are mediated by a zinc ion (Zn2+). The overall fold of huIFN-alpha(2b) is most similar to the structure of muIFN-beta. Unique to huIFN-alpha(2b) is a 3(10) helix in the AB loop which is held to the core of the molecule by a disulfide bond.Conclusions: The structure of huIFN-alpha(2b) provides an accurate model for analysis of the >15 related type I interferon molecules, HuIFN-alpha(2b) displays considerable structural similarity with muIFN-beta, interleukin-10 and interferon-gamma, which also bind related class 2 cytokine receptors. From these structural comparisons and numerous studies on the effects of mutations on biological activity, we have identified protein surfaces that appear to be important in receptor activation, This study also reveals the potential biological importance of the huIFN-alpha(2b) dimer.