肽
β淀粉样蛋白
立体化学
细胞生物学
细胞毒性T细胞
分子
组合化学
生物化学
作者
Qin Cao,Woo Shik Shin,Henry Chan,Celine K. Vuong,Bethany Dubois,Binsen Li,Kevin A. Murray,Michael R. Sawaya,Juli Feigon,Douglas L. Black,David Eisenberg,Lin Jiang
出处
期刊:Nature Chemistry
[Springer Nature]
日期:2018-10-08
卷期号:10 (12): 1213-1221
被引量:26
标识
DOI:10.1038/s41557-018-0147-z
摘要
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.
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