Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham NG7 2UH, UK; Centre of Membrane Proteins and Receptors, Universities of Birmingham and Nottingham, The Midlands, UK; Medicine Design, Medicinal Science and Technology, GlaxoSmithKline, Stevenage SG1 2NY, UK.
Protein and Cellular Sciences, Medicinal Science and Technology, GlaxoSmithKline, Stevenage SG1 2NY, UK.
Cell Chem Biol. 2022 Jan 20;29(1):19-29.e6. doi: 10.1016/j.chembiol.2021.05.002. Epub 2021 May 25.
Interleukin-23 (IL-23) is a pro-inflammatory cytokine involved in the host defense against pathogens but is also implicated in the development of several autoimmune disorders. The IL-23 receptor has become a key target for drug discovery, but the exact mechanism of the receptor ligand interaction remains poorly understood. In this study the affinities of IL-23 for its individual receptor components (IL23R and IL12Rβ1) and the heteromeric complex formed between them have been measured in living cells using NanoLuciferase-tagged full-length proteins. Here, we demonstrate that TAMRA-tagged IL-23 has a greater than 7-fold higher affinity for IL12Rβ1 than IL23R. However, in the presence of both receptor subunits, IL-23 affinity is increased more than three orders of magnitude to 27 pM. Furthermore, we show that IL-23 induces a potent change in the position of the N-terminal domains of the two receptor subunits, consistent with a conformational change in the heteromeric receptor structure.
白细胞介素-23（IL-23）是一种促炎细胞因子，参与宿主对病原体的防御，但也与几种自身免疫性疾病的发展有关。IL-23 受体已成为药物发现的关键靶点，但受体配体相互作用的确切机制仍知之甚少。在这项研究中，使用 NanoLuciferase 标记的全长蛋白在活细胞中测量了 IL-23 与其各个受体成分（IL23R 和 IL12Rβ1）以及它们之间形成的异源二聚体复合物的亲和力。在这里，我们证明 TAMRA 标记的 IL-23 对 IL12Rβ1 的亲和力比对 IL23R 高 7 倍以上。然而，在存在两个受体亚基的情况下，IL-23 的亲和力增加了三个数量级以上，达到 27 pM。此外，我们表明，IL-23 诱导两个受体亚基的 N 端结构域位置发生强烈变化，这与异源二聚体受体结构的构象变化一致。
Zotero 插件
