Cellular signaling via binding of the cytokines IL‐36α, β, and γ along with binding of the accessory protein IL‐36RAcP, to their cognate receptor IL‐36R is believed to play a major role in epithelial and immune cell‐mediated inflammation responses. Antagonizing the signaling cascade that results from these binding events via a directed monoclonal antibody provides an opportunity to suppress such immune responses. We report here the molecular structure of a complex between an extracellular portion of human IL‐36R and a Fab derived from a high affinity anti‐IL‐36R neutralizing monoclonal antibody at 2.3 Å resolution. This structure, the first of IL‐36R, reveals similarities with other structurally characterized IL‐1R family members and elucidates the molecular determinants leading to the high affinity binding of the monoclonal antibody. The structure of the complex reveals that the epitope recognized by the Fab is remote from both the putative ligand and accessory protein binding interfaces on IL‐36R, suggesting that the functional activity of the antibody is noncompetitive for these binding events.

中文翻译：

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X射线晶体结构定位了IL-36R拮抗剂单克隆抗体抑制与Ig1和Ig2细胞外结构域相互作用的机制。

通过细胞因子IL‐36α，β和γ的结合以及辅助蛋白IL‐36RAcP与它们的同源受体IL‐36R的结合，细胞信号传导被认为在上皮和免疫细胞介导的炎症反应中起主要作用。通过定向单克隆抗体拮抗由这些结合事件产生的信号级联反应提供了抑制这种免疫应答的机会。我们在这里报告了人IL‐36R细胞外部分与Fab的复合物的分子结构，该抗体源自2.3Å分辨率的高亲和力抗IL‐36R中和性单克隆抗体。这种结构是IL‐36R的第一个结构，揭示了与其他具有结构特征的IL‐1R家族成员的相似性，并阐明了导致单克隆抗体高亲和力结合的分子决定簇。