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Inhibiting amyloid-β cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design


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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Data availability

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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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Change history

  • 12 November 2018

    In the version of this Article originally published online, the upper right panel of Fig. 5a was mistakenly a repeat of the lower right panel. This has now been corrected in all versions of the Article.


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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.

Author information

Q.C., D.S.E. and L.J. conceived and designed the experiments. Q.C., W.S.S., H.C., C.K.V., B.D. and B.L. performed the experiments. W.S.S., B.D., K.A.M. and L.J. performed computational docking and structure-guided selection of small molecules. H.C. and J.F. performed and analysed NMR experiments. B.L. and L.J. performed and analysed circular dichroism experiments. C.K.V. and D.L.B. cultured primary neurons. Q.C. and M.R.S. solved the structure of the LilrB2 and benzamidine complex. All authors discussed the results and commented on the manuscript. Q.C., D.S.E. and L.J. analysed the data and co-wrote the paper.

Competing interests

D.S.E. is an advisor and equity shareholder in ADDRx.

Correspondence to David S. Eisenberg or Lin Jiang.

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    Methods and materials, Supplementary Figures 1–7, and Supplementary Table 1–4

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Fig. 1: The 16KLVFFA21 segment of Aβ binds to LilrB2 D1D2.
Fig. 2: Crystal structure of LilrB2 D1D2 complexed with benzamidine.
Fig. 3: Mutagenesis studies and Rosetta docking validate the Aβ binding sites on LilrB2.
Fig. 4: Selected small molecules inhibit the Aβ–LilrB2 interaction in vitro.
Fig. 5: Selected inhibitors block LilrB2-induced cell attachment and inhibit toxicity of Aβ.
Fig. 6: Validation of ALI6 using primary neurons.