Department of Biology, University of Konstanz, 78457 Konstanz, Germany.
Structure. 2010 Oct 13;18(10):1342-52. doi: 10.1016/j.str.2010.05.017.
The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor involved in inflammatory processes and is associated with diabetic complications, tumor outgrowth, and neurodegenerative disorders. RAGE induces cellular signaling events upon binding of a variety of ligands, such as glycated proteins, amyloid-β, HMGB1, and S100 proteins. The X-ray crystal structure of the VC1 ligand-binding region of the human RAGE ectodomain was determined at 1.85 Å resolution. The VC1 ligand-binding surface was mapped onto the structure from titrations with S100B monitored by heteronuclear NMR spectroscopy. These NMR chemical shift perturbations were used as input for restrained docking calculations to generate a model for the VC1-S100B complex. Together, the arrangement of VC1 molecules in the crystal and complementary biochemical studies suggest a role for self-association in RAGE function. Our results enhance understanding of the functional outcomes of S100 protein binding to RAGE and provide insight into mechanistic models for how the receptor is activated.
晚期糖基化终产物受体（RAGE）是一种模式识别受体，参与炎症过程，并与糖尿病并发症、肿瘤生长和神经退行性疾病有关。RAGE 在与各种配体（如糖化蛋白、淀粉样蛋白-β、HMGB1 和 S100 蛋白）结合后，会引发细胞信号事件。通过异核 NMR 光谱监测 S100B 的滴定，将 VC1 配体结合区域的人 RAGE 外域的 X 射线晶体结构解析至 1.85Å 分辨率。将 VC1 配体结合表面映射到结构上，通过异核 NMR 光谱监测 S100B 的滴定。这些 NMR 化学位移扰动被用作约束对接计算的输入，以生成 VC1-S100B 复合物的模型。总之，晶体中 VC1 分子的排列和互补的生化研究表明，自缔合在 RAGE 功能中起作用。我们的研究结果增强了对 S100 蛋白与 RAGE 结合的功能结果的理解，并为受体如何被激活的机制模型提供了线索。
