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Crystal structure of LIR-2 (ILT4) at 1.8 Å: differences from LIR-1 (ILT2) in regions implicated in the binding of the Human Cytomegalovirus class I MHC homolog UL18

Willcox, Benjamin E. and Thomas, Leonard M. and Chapman, Tara L. and Heikema, Astrid P. and West, Anthony P., Jr. and Bjorkman, Pamela J. (2002) Crystal structure of LIR-2 (ILT4) at 1.8 Å: differences from LIR-1 (ILT2) in regions implicated in the binding of the Human Cytomegalovirus class I MHC homolog UL18. BMC Structural Biology, 2 . Art. No. 6. ISSN 1472-6807. PMCID PMC130215. doi:10.1186/1472-6807-2-6.

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Background: Leukocyte Immunoglobulin-like Receptor-1 (LIR-1) and LIR-2 (also known as ILT2 and ILT4 respectively) are highly related cell surface receptors that bind a broad range of class I MHC molecules with low (μM) affinities. Expressed on monocytic cells and macrophages, both molecules transmit inhibitory signals after binding ligands. In addition to binding host class I MHC, the LIR-1 molecule, which is also expressed on lymphoid tissues, binds with a high (nM) affinity to UL18, a class I MHC homolog encoded by Human Cytomegalovirus (HCMV). In comparison, LIR-2 binds UL18 only weakly (μM K_D). To understand how HCMV preferentially targets the more broadly expressed LIR-1 molecule, we determined the crystal structure of a ligand-binding fragment of LIR-2, and compared this to the existing high-resolution crystal structure of LIR-1. Results: Recombinant LIR-2 (domains 1 and 2) was produced in E. coli and crystallized using streak seeding to optimize the crystal morphology. A data set complete to 1.8 Å was collected at 100 K from a single crystal in the P4_12_12 spacegroup. The structure was solved by molecular replacement, using a search model based on the LIR-1 structure. Conclusions: The overall structure of LIR-2 D1D2 resembles both LIR-1, and Killer Inhibitory Receptors, in that the A strand in each domain forms hydrogen bonds to both β sheets, and there is a sharp angle between the two immunoglobulin-like domains. However, differences from LIR-1 are observed in each domain, with two key changes apparent in the ligand-binding domain, D1. The region corresponding to the residue 44–57 helix of LIR-1 adopts a topology distinct from that of both LIR-1 and the KIR structures, involving a shortened 3_(10) helix. Secondly, the predicted UL18 binding region of LIR-1 is altered substantially in LIR-2: the 76–84 loop mainchain is displaced 11 Å with respect to LIR-1, and Tyrosine 38 adopts an alternative rotamer conformation. In summary, the structure of LIR-2 has revealed significant differences to LIR-1, including ones that may help to explain the >1000-fold lower affinity of LIR-2 for UL18.

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Bjorkman, Pamela J.0000-0002-2277-3990
Additional Information:© 2002 Willcox et al; licensee BioMed Central Ltd. This article is published in Open Access: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL. BEW expressed, purified and produced high quality crystals of LIR-2, carried out data collection and processing, structure solution, refinement and analysis and also wrote the manuscript. LMT carried out the latter stages of refinement and aided structural analyses. TLC produced initial microcrystals of LIR-2. APH carried out molecular cloning of the LIR-2 expression construct. APW provided help during data collection and processing, and critical scientific discussions. PJB conceived of the study, participated in its design and coordination, and provided financial support. Acknowledgements: We thank Drs Z.A. Hamburger, C. A. O'Callaghan and W.L. Martin for assistance with crystallographic software and valuable scientific discussions; D. Cosman for LIR-2 cDNA; S. Rowland-Jones for the kind gift of chinchilla whiskers; and members of the Bjorkman laboratory for critical reading of the manuscript. BEW is supported by a Wellcome Trust Traveling Fellowship (Grant code GR059939MF). Requests for coordinates should be addressed to BEW.
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Wellcome TrustGR059939MF
PubMed Central ID:PMC130215
Record Number:CaltechAUTHORS:WILbmcsb02
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Official Citation:Crystal structure of LIR-2 (ILT4) at 1.8 Å: differences from LIR-1 (ILT2) in regions implicated in the binding of the Human Cytomegalovirus class I MHC homolog UL18 Benjamin E Willcox, Leonard M Thomas, Tara L Chapman, Astrid P Heikema, Anthony P WestJr and Pamela J Bjorkman BMC Structural Biology 2002 2:6 DOI: 10.1186/1472-6807-2-6
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:311
Deposited By: Archive Administrator
Deposited On:18 May 2005
Last Modified:08 Nov 2021 19:01

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