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Structural basis for antagonism of human interleukin 18 by poxvirus interleukin 18-binding protein

Author:
Krumm, Brian, Meng, Xiangzhi, Li, Yongchao, Xiang, Yan, Deng, Junpeng
Source:
Proceedings of the National Academy of Sciences of the United States of America 2008 v.105 no.52 pp. 20711-20715
ISSN:
0027-8424
Subject:
Ectromelia virus, Variola virus, antagonists, autoimmune diseases, crystal structure, humans, hydrogen bonding, hydrophobicity, immune response, inflammation, interleukin-18, microorganisms, sequence homology, virulence
Abstract:
Human interleukin-18 (hIL-18) is a cytokine that plays an important role in inflammation and host defense against microbes. Its activity is regulated in vivo by a naturally occurring antagonist, the human IL-18-binding protein (IL-18BP). Functional homologs of human IL-18BP are encoded by all orthopoxviruses, including variola virus, the causative agent of smallpox. They contribute to virulence by suppressing IL-18-mediated immune responses. Here, we describe the 2.0-Å resolution crystal structure of an orthopoxvirus IL-18BP, ectromelia virus IL-18BP (ectvIL-18BP), in complex with hIL-18. The hIL-18 structure in the complex shows significant conformational change at the binding interface compared with the structure of ligand-free hIL-18, indicating that the binding is mediated by an induced-fit mechanism. EctvIL-18BP adopts a canonical Ig fold and interacts via one edge of its β-sandwich with 3 cavities on the hIL-18 surface through extensive hydrophobic and hydrogen bonding interactions. Most of the ectvIL-18BP residues that participate in these interactions are conserved in both human and viral homologs, explaining their functional equivalence despite limited sequence homology. EctvIL-18BP blocks a putative receptor-binding site on IL-18, thus preventing IL-18 from engaging its receptor. Our structure provides insights into how IL-18BPs modulate hIL-18 activity. The revealed binding interface provides the basis for rational design of inhibitors against orthopoxvirus IL-18BP (for treating orthopoxvirus infection) or hIL-18 (for treating certain inflammatory and autoimmune diseases).
Agid:
2362704