Inhibiting amyloid-β cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design
| Autor: | Woo Shik Shin, Douglas L. Black, Qin Cao, Lin Jiang, Kevin A. Murray, Henry Chan, David Eisenberg, Binsen Li, Bethany Dubois, Celine K. Vuong, Juli Feigon, Michael R. Sawaya |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cell Survival General Chemical Engineering Immunoglobulin domain Article Small Molecule Libraries Mice Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Alzheimer Disease Cell surface receptor Animals Humans Structure–activity relationship Receptors Immunologic Binding site Cytotoxicity Receptor Neurons Amyloid beta-Peptides Membrane Glycoproteins Dose-Response Relationship Drug Molecular Structure Chemistry General Chemistry neuronal cell surface receptor Small molecule structure-based design 030104 developmental biology Docking (molecular) Drug Design Biophysics Alzheimer’s disease 030217 neurology & neurosurgery |
| Zdroj: | Nature chemistry |
| ISSN: | 1755-4349 1755-4330 |
| Popis: | Inhibiting the interaction between ß-amyloid (Aß) and a neuronal cell surface receptor, LilrB2, has been suggested as a potential route for treating Alzheimer’s disease (AD). Supporting this approach, AD-like symptoms are reduced in mouse models following genetic depletion of the LilrB2 homolog. In its pathogenic, oligomeric state, Aß binds to LilrB2, triggering a pathway to synaptic loss. Here we identified the LilrB2 binding moieties of Aß (16KLVFFA21) and identified 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 sidechains of KLVFFA. These pockets were confirmed to be 16KLVFFA21 binding sites by mutagenesis. Rosetta docking revealed a plausible geometry for the Aß-LilrB2 complex and assisted with the structure-guided selection of small molecule inhibitors. These molecules inhibit Aß-LilrB2 interactions in vitro and on the cell surface and reduce Aß cytotoxicity, which suggests these inhibitors are potential therapeutic leads against AD. Graphical Abstract |
| Databáze: | OpenAIRE |
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