PDBsum entry 3f62

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protein Protein-protein interface(s) links
Cytokine PDB id
Protein chains
108 a.a. *
145 a.a. *
Waters ×120
* Residue conservation analysis
PDB id:
Name: Cytokine
Title: Crystal structure of human il-18 in complex with ectromelia 18 binding protein
Structure: Interleukin 18 binding protein. Chain: a. Fragment: unp residues 21-126. Engineered: yes. Interleukin-18. Chain: b. Fragment: unp residues 37-193. Synonym: il-18, interferon-gamma-inducing factor, ifn-gamma factor, interleukin-1 gamma, il-1 gamma, iboctadekin.
Source: Ectromelia virus. Organism_taxid: 12643. Expressed in: escherichia coli. Expression_system_taxid: 562. Homo sapiens. Human. Organism_taxid: 9606. Gene: il18, igif, il1f4. Expression_system_taxid: 562
2.00Å     R-factor:   0.191     R-free:   0.235
Authors: B.E.Krumm,Y.Li,J.Deng
Key ref:
B.Krumm et al. (2008). Structural basis for antagonism of human interleukin 18 by poxvirus interleukin 18-binding protein. Proc Natl Acad Sci U S A, 105, 20711-20715. PubMed id: 19104048 DOI: 10.1073/pnas.0809086106
05-Nov-08     Release date:   06-Jan-09    
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Protein chain
Pfam   ArchSchema ?
Q85319  (Q85319_9POXV) -  EVM013
138 a.a.
108 a.a.*
Protein chain
Pfam   ArchSchema ?
Q14116  (IL18_HUMAN) -  Interleukin-18
193 a.a.
145 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 12 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular space   1 term 


DOI no: 10.1073/pnas.0809086106 Proc Natl Acad Sci U S A 105:20711-20715 (2008)
PubMed id: 19104048  
Structural basis for antagonism of human interleukin 18 by poxvirus interleukin 18-binding protein.
B.Krumm, X.Meng, Y.Li, Y.Xiang, J.Deng.
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).
  Selected figure(s)  
Figure 2.
HIL-18–ectvIL-18BP interface. (A) Three binding pockets on hIL-18 surface. (Center) EctvIL-18BP and hIL-18 complex in a top-down view as seen in Fig. 1; hIL18 is shown as surface presentation and colored gray, and ectvIL-18BP is drawn as a ribbon diagram with β-sheets colored in yellow. Binding sites A–C on the hIL-18 surface are colored red, orange, and cyan, respectively. EctvIL-18BP residues involved in binding hIL-18 are shown as sticks. (Insets) Interactions involved in the respective binding site between ectvIL-18BP and hIL-18. (B) Remodeling of hIL-18 at site A. The coloring scheme is the same as in Fig. 1C. Tyr-1, Lys-53, Ser-66, and Pro-57 are shown as sticks. Notice the drastic repositioning of the side chains of Tyr-1 and Lys-53 at the carboxyl terminus of hIL-18 upon binding ectvIL-18BP. (C and D) Results of the conformational change upon ectvIL-18BP binding, yielding a new binding cavity/pocket for Tyr-53 and Phe-67 of ectvIL-18BP (shown as sticks). The ligand-free hIL-18 is shown as a surface presentation in blue in C. The complexed hIL-18 in the current crystal structure is shown as surface model in green. Notice that the absence of Phe-67 pocket and the steric clash on Tyr-53 would occur with the ligand-free state of hIL-18. The 2 key hIL-18 residues, Lys-53 and Tyr-1 are labeled as bold italic letters.
Figure 3.
Mechanism by which ectvIL-18BP inhibits hIL-18. EctvIL-18BP blocks the putative hIL-18Rα-binding site. Human IL-18 is represented as a surface model as viewed from the top of the β-trefoil. EctvIL-18BP-binding sites A–C on hIL-18 are colored in red, orange, and cyan, respectively. Human IL-18 residues that are potentially shared between ectvIL-18BP and hIL-18Rα are colored in purple and span the 3 ectvIL-18BP-binding sites on hIL-18.
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
22902366 J.Elegheert, N.Bracke, P.Pouliot, I.Gutsche, A.V.Shkumatov, N.Tarbouriech, K.Verstraete, A.Bekaert, W.P.Burmeister, D.I.Svergun, B.N.Lambrecht, B.Vergauwen, and S.N.Savvides (2012).
Allosteric competitive inactivation of hematopoietic CSF-1 signaling by the viral decoy receptor BARF1.
  Nat Struct Mol Biol, 19, 938-947.
PDB codes: 3uez 3uf2 3uf5 4adf 4adq
20121409 C.Chirathaworn, P.Rianthavorn, N.Wuttirattanakowit, and Y.Poovorawan (2010).
Serum IL-18 and IL-18BP levels in patients with Chikungunya virus infection.
  Viral Immunol, 23, 113-117.  
20802483 D.Wang, S.Zhang, L.Li, X.Liu, K.Mei, and X.Wang (2010).
Structural insights into the assembly and activation of IL-1β with its receptors.
  Nat Immunol, 11, 905-911.
PDB code: 3o4o
21087098 S.Lee, S.Kim, S.Bae, J.Choi, J.Hong, S.Ryoo, H.Jhun, K.Hong, E.Kim, S.Jo, E.Her, and S.Kim (2010).
Development of isoform-specific monoclonal antibodies against human IL-18 binding protein.
  Hybridoma (Larchmt), 29, 517-524.  
20089642 Y.Li, X.Meng, Y.Xiang, and J.Deng (2010).
Structure function studies of vaccinia virus host range protein k1 reveal a novel functional surface for ankyrin repeat proteins.
  J Virol, 84, 3331-3338.
PDB code: 3kea
19836339 A.Lingel, T.M.Weiss, M.Niebuhr, B.Pan, B.A.Appleton, C.Wiesmann, J.F.Bazan, and W.J.Fairbrother (2009).
Structure of IL-33 and its interaction with the ST2 and IL-1RAcP receptors--insight into heterotrimeric IL-1 signaling complexes.
  Structure, 17, 1398-1410.
PDB code: 2kll
19946139 K.Van Vliet, M.R.Mohamed, L.Zhang, N.Y.Villa, S.J.Werden, J.Liu, and G.McFadden (2009).
Poxvirus proteomics and virus-host protein interactions.
  Microbiol Mol Biol Rev, 73, 730-749.  
19553661 M.A.Argiriadi, T.Xiang, C.Wu, T.Ghayur, and D.W.Borhani (2009).
Unusual water-mediated antigenic recognition of the proinflammatory cytokine interleukin-18.
  J Biol Chem, 284, 24478-24489.
PDB codes: 2vxt 2vxu 2vxv
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.