The structural basis for receptor recognition of human interleukin-18

Abstract

Interleukin (IL)-18 is a proinflammatory cytokine that belongs to the IL-1 family and plays an important role in inflammation. The uncontrolled release of this cytokine is associated with severe chronic inflammatory disease. IL-18 forms a signalling complex with the IL-18 receptor α (Rα) and β (Rβ) chains at the plasma membrane, which induces multiple inflammatory cytokines. Here, we present a crystal structure of human IL-18 bound to the two receptor extracellular domains. Generally, the receptors’ recognition mode for IL-18 is similar to IL-1β; however, certain notable differences were observed. The architecture of the IL-18 receptor second domain (D2) is unique among the other IL-1R family members, which presumably distinguishes them from the IL-1 receptors that exhibit a more promiscuous ligand recognition mode. The structures and associated biochemical and cellular data should aid in developing novel drugs to neutralize IL-18 activity.

Crystallization of interleukin-18 for structure-based inhibitor design

“…Further analysis of the SER mutant I and mutant III crystal structures revealed a nearly symmetrical crystal-packing interaction involving several binding-interface residues which are also found in the recent apo hIL-18 structure Tsutsumi et al, 2014) between their main-chain O and N atoms, respectively (Figs. 2d and 3d).…”

“…The first structure of hIL-18 was solved by solution NMR and other structures of hIL-18 have been determined either in complex with its cognate receptor(s), IL-18BPs or with hIL-18-specific antibodies (Kato et al, 2003;Krumm et al, 2008Krumm et al, , 2012Wei et al, 2014;Argiriadi et al, 2009;Tsutsumi et al, 2014). Apo hIL-18 has been recalcitrant to crystallization.…”

“…(b) Crystal structure of hIL-18 from PDB entry 3f62 drawn as a cartoon representation and colored green; ectvIL-18BP has been removed for clarity, revealing the opening of the hIL-18 -trefoil barrel. (c) Crystal structure of the IL-18 ternary complex shown as a ribbon diagram with IL-18R in cyan, IL-18R in magenta and IL-18 in green (PDB entry 3wo4; Tsutsumi et al, 2014). The colored spheres in (b) and (c) are the SER clusters: mutant I, red; mutant II, yellow; mutants III, IV and V, blue.…”

“…As an immune-evasion strategy, homologs of IL-18BPs are also encoded by many poxviruses such as Molluscum contagiosum virus, orthopoxviruses such as Variola virus (the causative agent of smallpox) and yatapoxviruses such as Yaba-like disease virus (YLDV). The recent crystal structures of hIL-18 in complex with Ectromelia virus (ectv; Krumm et al, 2008) and YLDV (Krumm et al, 2012) IL-18BP revealed a conserved mechanism of hIL-18 inhibition through direct competition for a common binding site with the hIL-18 primary receptor (hIL-18R) domain 3 (D3; Tsutsumi et al, 2014;Wei et al, 2014).…”

Structural and Functional Attributes of the Interleukin-36 Receptor

“…The crystal structures of ECDs of IL-1R, IL-18R, and IL-33R ECD have been elucidated (12)(13)(14)(15). The ECDs of IL-1R, IL-18R, and IL-33R and their co-receptors IL-1RAcP all contain three immunoglobulin (Ig)-like domains.…”