Sayago Cristina, Gonzalez Valcarcel Isabel C, Qian Yuewei, Lee John, Alsina-Fernandez Jorge, Fite Nathan C, Carrillo Juan J, Zhang Feiyu F, Chalmers Michael J, Dodge Jeffrey A, Broughton Howard, Espada Alfonso
Centro de Investigación Lilly S.A., 28108-Alcobendas, Spain.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, United States.
ACS Med Chem Lett. 2018 Aug 1;9(9):912-916. doi: 10.1021/acsmedchemlett.8b00255. eCollection 2018 Sep 13.
Molecular characterization of the binding epitope of IL-23R and its cognate cytokine IL-23 is paramount to understand the role in autoimmune diseases and to support the discovery of new inhibitors of this protein-protein interaction. Our results revealed that HDX-MS was able to identify the binding epitope of IL-23R:IL-23, which opened the way to evaluate a peptide macrocycle described in the literature as disrupter of this autoimmune target. Thus, the characterization of the interactions of this chemotype by HDX-MS in combination with computational approaches was achieved. To our knowledge, this is the first reported structural evidence regarding the site where a small compound binds to IL-23R.
白细胞介素-23受体（IL-23R）与其同源细胞因子IL-23结合表位的分子特征，对于理解其在自身免疫性疾病中的作用以及支持发现这种蛋白质-蛋白质相互作用的新抑制剂至关重要。我们的结果表明，氢氘交换质谱（HDX-MS）能够识别IL-23R:IL-23的结合表位，这为评估文献中描述的作为这种自身免疫靶点破坏剂的肽大环化合物开辟了道路。因此，通过HDX-MS结合计算方法实现了对这种化学类型相互作用的表征。据我们所知，这是首次报道关于一种小分子化合物与IL-23R结合位点的结构证据。
