Schreuder H, Tardif C, Trump-Kallmeyer S, Soffientini A, Sarubbi E, Akeson A, Bowlin T, Yanofsky S, Barrett R W
Marion Merrell Dow Research Institute, Strasbourg, France.
Nature. 1997 Mar 13;386(6621):194-200. doi: 10.1038/386194a0.
Inflammation, regardless of whether it is provoked by infection or by tissue damage, starts with the activation of macrophages which initiate a cascade of inflammatory responses by producing the cytokines interleukin-1 (IL-1) and tumour necrosis factor-alpha (ref. 1). Three naturally occurring ligands for the IL-1 receptor (IL1R) exist: the agonists IL-1alpha and IL-1beta and the IL-1-receptor antagonist IL1RA (ref. 2). IL-1 is the only cytokine for which a naturally occurring antagonist is known. Here we describe the crystal structure at 2.7 A resolution of the soluble extracellular part of type-I IL1R complexed with IL1RA. The receptor consists of three immunoglobulin-like domains. Domains 1 and 2 are tightly linked, but domain three is completely separate and connected by a flexible linker. Residues of all three domains contact the antagonist and include the five critical IL1RA residues which were identified by site-directed mutagenesis. A region that is important for biological function in IL-1beta, the 'receptor trigger site' is not in direct contact with the receptor in the IL1RA complex. Modelling studies suggest that this IL-1beta trigger site might induce a movement of domain 3.
炎症，无论其是由感染还是组织损伤引发，均始于巨噬细胞的激活，巨噬细胞通过产生细胞因子白细胞介素-1（IL-1）和肿瘤坏死因子-α引发一系列炎症反应（参考文献1）。白细胞介素-1受体（IL1R）有三种天然存在的配体：激动剂IL-1α和IL-1β以及白细胞介素-1受体拮抗剂IL1RA（参考文献2）。IL-1是唯一已知存在天然拮抗剂的细胞因子。在此，我们描述了与IL1RA复合的I型IL1R可溶性细胞外部分分辨率为2.7埃的晶体结构。该受体由三个免疫球蛋白样结构域组成。结构域1和2紧密相连，但结构域3完全分开并通过一个柔性连接子相连。所有三个结构域的残基均与拮抗剂接触，包括通过定点诱变确定的五个关键IL1RA残基。在IL-1β中对生物学功能很重要的一个区域，即“受体触发位点”，在IL1RA复合物中不与受体直接接触。建模研究表明，这个IL-1β触发位点可能会诱导结构域3的移动。
