Structural basis for antagonism of human interleukin 18 by poxvirus interleukin 18-binding protein.
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-A 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 beta-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).
Krumm
Brian
B
Department of Biochemistry and Molecular Biology, Oklahoma State University, Stillwater, OK 74078, USA.
Meng
Xiangzhi
X
Li
Yongchao
Y
Xiang
Yan
Y
Deng
Junpeng
J
D001665:Binding Sites / Q000502:physiology; D004481:Ectromelia virus / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D017510:Protein Folding; D020836:Protein Structure, Quaternary / Q000502:physiology; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000737:chemistry* / Q000276:immunology / Q000378:metabolism
D036341:Intercellular Signaling Peptides and Proteins; D020382:Interleukin-18; D014764:Viral Proteins; C118370:interleukin-18 binding protein