PDBsum entry: 3f62

Cytokine

PDB id: 3f62

Contents

Protein chains

108 a.a. *

145 a.a. *

Waters ×120

* Residue conservation analysis

PDB id:

3f62

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

Resolution:

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

Date:

05-Nov-08 Release date: 06-Jan-09

Protein chain

Q85319  (Q85319_9POXV) -  EVM013

Seq: 138 a.a.

Struc: 108 a.a.*

Protein chain

Q14116  (IL18_HUMAN) -  Interleukin-18

Seq: 193 a.a.

Struc: 145 a.a.*

* PDB and UniProt seqs differ at 12 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 

• 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.

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).

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.