CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
Nat Commun. 2022 Apr 1;13(1):1775. doi: 10.1038/s41467-022-29361-x.
Formyl peptide receptor 2 (FPR2) has been shown to mediate the cytotoxic effects of the β amyloid peptide Aβ and serves as a receptor for humanin, a peptide that protects neuronal cells from damage by Aβ, implying its involvement in the pathogenesis of Alzheimer's disease (AD). However, the interaction pattern between FPR2 and Aβ or humanin remains unknown. Here we report the structures of FPR2 bound to G and Aβ or N-formyl humanin (fHN). Combined with functional data, the structures reveal two critical regions that govern recognition and activity of Aβ and fHN, including a polar binding cavity within the receptor helical bundle and a hydrophobic binding groove in the extracellular region. In addition, the structures of FPR2 and FPR1 in complex with different formyl peptides were determined, providing insights into ligand recognition and selectivity of the FPR family. These findings uncover key factors that define the functionality of FPR2 in AD and other inflammatory diseases and would enable drug development.
甲酰肽受体 2（FPR2）已被证明介导β淀粉样肽 Aβ 的细胞毒性作用，并作为人源神经保护素（HN）的受体，HN 是一种能保护神经元细胞免受 Aβ 损伤的肽，这意味着它参与了阿尔茨海默病（AD）的发病机制。然而，FPR2 与 Aβ 或人源神经保护素（HN）之间的相互作用模式仍不清楚。在这里，我们报告了 FPR2 与 G 和 Aβ 或 N-甲酰基人源神经保护素（fHN）结合的结构。结合功能数据，这些结构揭示了两个关键区域，它们控制着 Aβ 和 fHN 的识别和活性，包括受体螺旋束内的极性结合腔和细胞外区域的疏水性结合槽。此外，还确定了 FPR2 和 FPR1 与不同甲酰肽复合物的结构，为 FPR 家族的配体识别和选择性提供了深入了解。这些发现揭示了定义 FPR2 在 AD 和其他炎症性疾病中的功能的关键因素，并将能够促进药物开发。
