3F62

Crystal Structure of Human IL-18 in complex with Ectromelia virus IL-18 Binding Protein

Summary for 3F62

• Entry DOI: 10.2210/pdb3f62/pdb
• Descriptor: Interleukin 18 binding protein, Interleukin-18 (3 entities in total)
• Functional Keywords: immunoglobulin, il-18, beta trefoil, cytokine, secreted
• Biological source: Ectromelia virus; More
• Cellular location: Secreted: Q14116
• Total number of polymer chains: 2
• Total formula weight: 30600.54

Authors

Krumm, B.E.,Li, Y.,Deng, J. (deposition date: 2008-11-05, release date: 2009-01-06, Last modification date: 2024-11-20)

Primary citation

Krumm, B.,Meng, X.,Li, Y.,Xiang, Y.,Deng, J.
Structural basis for antagonism of human interleukin 18 by poxvirus interleukin 18-binding protein.
Proc.Natl.Acad.Sci.USA, 105:20711-20715, 2008

PubMed 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-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).

PubMed: 19104048
DOI: 10.1073/pnas.0809086106

Experimental method

X-RAY DIFFRACTION (2 Å)