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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The crystal structure reported here, LilrB2 D1D2 complexed with benzamidine, and the corresponding diffraction data have been deposited to the Protein Data Bank (PDB) with the accession code 6BCS. All other data are available upon reasonable request to the authors.
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The authors thank C. Shatz for providing the LilrB2 plasmid. This work is based on research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences from the National Institutes of Health (P41 GM103403). The Pilatus 6M detector on the 24-ID-C beamline is funded by a NIH-ORIP HEI grant (S10 RR029205). This research used resources from the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. L.J. is supported by UCLA departmental recruitment funds. The authors also acknowledge NIH AG 054022 and DOE DE-FC02-02ER63421 for support.