PDBsum entry 6bcs

Immune system

PDB id: 6bcs

Contents

Protein chain

196 a.a.

Ligands

BEN ×4

DMS ×2

Metals

_CL ×2

Waters ×62

PDB id:

6bcs

Name:

Immune system

Title:

Lilrb2 d1d2 domains complexed with benzamidine

Structure:

Leukocyte immunoglobulin-like receptor subfamily b member 2. Chain: a. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: lilrb2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.

Resolution:

2.10Å R-factor: 0.187 R-free: 0.233

Authors:

Q.Cao,M.R.Sawaya,D.S.Eisenberg

Key ref:

Q.Cao et al. (2018). Inhibiting amyloid-β cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design. Nat Chem, 10, 1213-1221. PubMed id: 30297750

Date:

20-Oct-17 Release date: 05-Sep-18

Protein chain

Q8N423  (LIRB2_HUMAN) -  Leukocyte immunoglobulin-like receptor subfamily B member 2 from Homo sapiens

Seq: 597 a.a.

Struc: 196 a.a.

Nat Chem 10:1213-1221 (2018)

PubMed id: 30297750

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

Q.Cao, W.S.Shin, H.Chan, C.K.Vuong, B.Dubois, B.Li, K.A.Murray, M.R.Sawaya, J.Feigon, D.L.Black, D.S.Eisenberg, L.Jiang.

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.