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Nat Chem. 2018 Dec;10(12):1213-1221. doi: 10.1038/s41557-018-0147-z. Epub 2018 Oct 8.

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

Author information

1
Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute and Howard Hughes Medical Institute, UCLA, Los Angeles, CA, USA.
2
Department of Neurology, Molecular Biology Institute and Brain Research Institute, UCLA, Los Angeles, CA, USA.
3
Department of Chemistry and Biochemistry, UCLA, Los Angeles, CA, USA.
4
Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
5
Systems Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA.
6
Division of Applied Mathematics, Brown University, Providence, RI, USA.
7
Departments of Chemistry and Biochemistry and Biological Chemistry, UCLA-DOE Institute and Howard Hughes Medical Institute, UCLA, Los Angeles, CA, USA. david@mbi.ucla.edu.
8
Department of Neurology, Molecular Biology Institute and Brain Research Institute, UCLA, Los Angeles, CA, USA. jianglin@ucla.edu.

Abstract

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.

PMID:
30297750
PMCID:
PMC6250578
[Available on 2019-04-08]
DOI:
10.1038/s41557-018-0147-z

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