Inhibiting the interaction between amyloid-β (Aβ) and a neuronal cell surface receptor, LilrB2, has been suggested as a potential route for treating Alzheimer’s disease. Supporting this approach, Alzheimer’s-like symptoms are reduced in mouse models following genetic depletion of the LilrB2 homologue. In its pathogenic, oligomeric state, Aβ binds to LilrB2, triggering a pathway to synaptic loss. Here we identify the LilrB2 binding moieties of Aβ (¹⁶KLVFFA²¹) and identify its binding site on LilrB2 from a crystal structure of LilrB2 immunoglobulin domains D1D2 complexed to small molecules that mimic phenylalanine residues. In this structure, we observed two pockets that can accommodate the phenylalanine side chains of KLVFFA. These pockets were confirmed to be ¹⁶KLVFFA²¹ binding sites by mutagenesis. Rosetta docking revealed a plausible geometry for the Aβ–LilrB2 complex and assisted with the structure-guided selection of small molecule inhibitors. These molecules inhibit Aβ–LilrB2 interactions in vitro and on the cell surface and reduce Aβ cytotoxicity, which suggests these inhibitors are potential therapeutic leads against Alzheimer’s disease.

抑制淀粉样蛋白-β (Aβ) 与神经元细胞表面受体 LilrB2 之间的相互作用已被认为是治疗阿尔茨海默病的潜在途径。支持这种方法，在 LilrB2 同系物的遗传耗竭后，小鼠模型中的阿尔茨海默病样症状有所减轻。在其致病性寡聚状态下，Aβ 与 LilrB2 结合，触发突触丢失的途径。在这里，我们鉴定了 Aβ ( ¹⁶ KLVFFA ²¹ )的 LilrB2 结合部分，并从与模拟苯丙氨酸残基的小分子复合的 LilrB2 免疫球蛋白域 D1D2 的晶体结构鉴定了其在 LilrB2 上的结合位点。在这个结构中，我们观察到两个口袋可以容纳 KLVFFA 的苯丙氨酸侧链。这些口袋被确认为¹⁶KLVFFA ²¹结合位点通过诱变。Rosetta 对接揭示了 Aβ-LilrB2 复合物的合理几何形状，并有助于小分子抑制剂的结构引导选择。这些分子在体外和细胞表面抑制 Aβ-LilrB2 相互作用并降低 Aβ 细胞毒性，这表明这些抑制剂是针对阿尔茨海默病的潜在治疗方法。