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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structural Basis For Antagonism Of Human Interleukin18 By Poxvirus Interleukin 18-binding Protein
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Structural Basis For Antagonism Of Human Interleukin18 By Poxvirus Interleukin 18-binding Protein

机译：痘病毒白细胞介素18结合蛋白对人白细胞介素18拮抗作用的结构基础

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摘要

Human interleukin-18 (hIL-18) is a cytokine that plays an important role in inflammation and host defense against microbes. Its activity is regulated in vivo by a naturally occurring antagonist, the human IL-18-binding protein (IL-18BP). Functional homologs of human IL-18 BP are encoded by all orthopoxviruses, including variola virus, the causative agent of smallpox. They contribute to virulence by suppressing IL-18-mediated immune responses. Here, we describe the 2.0-A resolution crystal structure of an orthopoxvirus IL-18BP, ectromelia virus IL-18BP (ectvlL-18BP), in complex with hlL-18. The hlL-18 structure in the complex shows significant conformational change at the binding interface compared with the structure of ligand-free hlL-18, indicating that the binding is mediated by an induced-fit mechanism. EctvlL-18BP adopts a canonical Ig fold and interacts via one edge of its β-sandwich with 3 cavities on the hIL-18 surface through extensive hydrophobic and hydrogen bonding interactions. Most of the ectvlL-18BP residues that participate in these interactions are conserved in both human and viral homologs, explaining their functional equivalence despite limited sequence homology. EctvlL-18BP blocks a putative receptor-binding site on IL-18, thus preventing IL-18 from engaging its receptor. Our structure provides insights into how IL-18BPs modulate hlL-18 activity. The revealed binding interface provides the basis for rational design of inhibitors against orthopoxvirus IL-18BP (for treating orthopoxvirus infection) or hIL-18 (for treating certain inflammatory and autoimmune diseases).
机译：人白介素18（hIL-18）是一种细胞因子，在炎症和宿主防御微生物中起着重要作用。其活性在体内受天然拮抗剂人IL-18结合蛋白（IL-18BP）调节。人IL-18 BP的功能同源物由所有正痘病毒（包括天花的病原体天花病毒）编码。它们通过抑制IL-18介导的免疫反应来促进毒性。在这里，我们描述了与hlL-18结合的正痘病毒IL-18BP，念珠菌病毒IL-18BP（ectvlL-18BP）的2.0-A分辨率晶体结构。与不含配体的hlL-18的结构相比，复合物中的hlL-18结构在结合界面显示出显着的构象变化，表明该结合是通过诱导拟合机制介导的。 EctvlL-18BP具有典型的Ig折叠，并通过其β三明治的一个边缘与hIL-18表面上的3个空腔通过广泛的疏水和氢键相互作用进行相互作用。参与这些相互作用的大多数ectvLL-18BP残基在人类和病毒同源物中均是保守的，尽管序列同源性有限，但仍可解释其功能等效性。 EctvlL-18BP阻断了IL-18上一个假定的受体结合位点，从而阻止IL-18与其受体结合。我们的结构提供了有关IL-18BP如何调节hlL-18活性的见解。揭示的结合界面为合理设计抗正痘病毒IL-18BP（用于治疗正痘病毒感染）或hIL-18（用于治疗某些炎性和自身免疫性疾病）的抑制剂提供了基础。

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