Vigers G P, Anderson L J, Caffes P, Brandhuber B J
Amgen Inc., Boulder, Colorado 80301, USA.
Nature. 1997 Mar 13;386(6621):190-4. doi: 10.1038/386190a0.
Interleukin-1 (IL-1) is an important mediator of inflammatory disease. The IL-1 family currently consists of two agonists, IL-1alpha and IL-1beta, and one antagonist, IL-1ra. Each of these molecules binds to the type I IL-1 receptor (IL1R). The binding of IL-1alpha or IL-1beta to IL1R is an early step in IL-1 signal transduction and blocking this interaction may therefore be a useful target for the development of new drugs. Here we report the three-dimensional structure of IL-1beta bound to the extracellular domain of IL1R (s-IL1R) at 2.5 A resolution. IL-1beta binds to s-IL1R with a 1:1 stoichiometry. The crystal structure shows that s-IL1R consists of three immunoglobulin-like domains which wrap around IL-1beta in a manner distinct from the structures of previously described cytokine-receptor complexes. The two receptor-binding regions on IL-1beta identified by site-directed mutagenesis both contact the receptor: one binds to the first two domains of the receptor, while the other binds exclusively to the third domain.
白细胞介素-1（IL-1）是炎症性疾病的重要介质。IL-1家族目前由两种激动剂IL-1α和IL-1β以及一种拮抗剂IL-1ra组成。这些分子中的每一个都与I型IL-1受体（IL1R）结合。IL-1α或IL-1β与IL1R的结合是IL-1信号转导的早期步骤，因此阻断这种相互作用可能是开发新药的一个有用靶点。在此，我们报告了以2.5埃分辨率解析的与IL1R胞外域（s-IL1R）结合的IL-1β的三维结构。IL-1β以1:1的化学计量比与s-IL1R结合。晶体结构表明，s-IL1R由三个免疫球蛋白样结构域组成，它们以一种不同于先前描述的细胞因子-受体复合物结构的方式围绕IL-1β。通过定点诱变确定的IL-1β上的两个受体结合区域均与受体接触：一个与受体的前两个结构域结合，而另一个仅与第三个结构域结合。
