6bcs

LilrB2 D1D2 domains complexed with benzamidineLilrB2 D1D2 domains complexed with benzamidine

Structural highlights

6bcs is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.1Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LIRB2_HUMAN Receptor for class I MHC antigens. Recognizes a broad spectrum of HLA-A, HLA-B, HLA-C and HLA-G alleles. Involved in the down-regulation of the immune response and the development of tolerance. Competes with CD8A for binding to class I MHC antigens. Inhibits FCGR1A-mediated phosphorylation of cellular proteins and mobilization of intracellular calcium ions.^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Inhibiting the interaction between amyloid-beta (Abeta) 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, Abeta binds to LilrB2, triggering a pathway to synaptic loss. Here we identify the LilrB2 binding moieties of Abeta ((16)KLVFFA(21)) 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 (16)KLVFFA(21) binding sites by mutagenesis. Rosetta docking revealed a plausible geometry for the Abeta-LilrB2 complex and assisted with the structure-guided selection of small molecule inhibitors. These molecules inhibit Abeta-LilrB2 interactions in vitro and on the cell surface and reduce Abeta cytotoxicity, which suggests these inhibitors are potential therapeutic leads against Alzheimer's disease.

Inhibiting amyloid-beta cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design.,Cao Q, Shin WS, Chan H, Vuong CK, Dubois B, Li B, Murray KA, Sawaya MR, Feigon J, Black DL, Eisenberg DS, Jiang L Nat Chem. 2018 Oct 8. pii: 10.1038/s41557-018-0147-z. doi:, 10.1038/s41557-018-0147-z. PMID:30297750^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Borges L, Hsu ML, Fanger N, Kubin M, Cosman D. A family of human lymphoid and myeloid Ig-like receptors, some of which bind to MHC class I molecules. J Immunol. 1997 Dec 1;159(11):5192-6. PMID:9548455
↑ Fanger NA, Cosman D, Peterson L, Braddy SC, Maliszewski CR, Borges L. The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in monocytes. Eur J Immunol. 1998 Nov;28(11):3423-34. PMID:9842885
↑ Chang CC, Ciubotariu R, Manavalan JS, Yuan J, Colovai AI, Piazza F, Lederman S, Colonna M, Cortesini R, Dalla-Favera R, Suciu-Foca N. Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol. 2002 Mar;3(3):237-43. Epub 2002 Jan 28. PMID:11875462 doi:10.1038/ni760
↑ Shiroishi M, Tsumoto K, Amano K, Shirakihara Y, Colonna M, Braud VM, Allan DS, Makadzange A, Rowland-Jones S, Willcox B, Jones EY, van der Merwe PA, Kumagai I, Maenaka K. Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8856-61. Epub 2003 Jul 9. PMID:12853576 doi:10.1073/pnas.1431057100
↑ Cao Q, Shin WS, Chan H, Vuong CK, Dubois B, Li B, Murray KA, Sawaya MR, Feigon J, Black DL, Eisenberg DS, Jiang L. Inhibiting amyloid-beta cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design. Nat Chem. 2018 Oct 8. pii: 10.1038/s41557-018-0147-z. doi:, 10.1038/s41557-018-0147-z. PMID:30297750 doi:http://dx.doi.org/10.1038/s41557-018-0147-z

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OCA

[1] Borges L, Hsu ML, Fanger N, Kubin M, Cosman D. A family of human lymphoid and myeloid Ig-like receptors, some of which bind to MHC class I molecules. J Immunol. 1997 Dec 1;159(11):5192-6. PMID:9548455

[2] Fanger NA, Cosman D, Peterson L, Braddy SC, Maliszewski CR, Borges L. The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in monocytes. Eur J Immunol. 1998 Nov;28(11):3423-34. PMID:9842885

[3] Chang CC, Ciubotariu R, Manavalan JS, Yuan J, Colovai AI, Piazza F, Lederman S, Colonna M, Cortesini R, Dalla-Favera R, Suciu-Foca N. Tolerization of dendritic cells by T(S) cells: the crucial role of inhibitory receptors ILT3 and ILT4. Nat Immunol. 2002 Mar;3(3):237-43. Epub 2002 Jan 28. PMID:11875462 doi:10.1038/ni760

[4] Shiroishi M, Tsumoto K, Amano K, Shirakihara Y, Colonna M, Braud VM, Allan DS, Makadzange A, Rowland-Jones S, Willcox B, Jones EY, van der Merwe PA, Kumagai I, Maenaka K. Human inhibitory receptors Ig-like transcript 2 (ILT2) and ILT4 compete with CD8 for MHC class I binding and bind preferentially to HLA-G. Proc Natl Acad Sci U S A. 2003 Jul 22;100(15):8856-61. Epub 2003 Jul 9. PMID:12853576 doi:10.1073/pnas.1431057100

[5] Cao Q, Shin WS, Chan H, Vuong CK, Dubois B, Li B, Murray KA, Sawaya MR, Feigon J, Black DL, Eisenberg DS, Jiang L. Inhibiting amyloid-beta cytotoxicity through its interaction with the cell surface receptor LilrB2 by structure-based design. Nat Chem. 2018 Oct 8. pii: 10.1038/s41557-018-0147-z. doi:, 10.1038/s41557-018-0147-z. PMID:30297750 doi:http://dx.doi.org/10.1038/s41557-018-0147-z

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