7AL7

The Crystal Structure of Human IL-18 in Complex With Human IL-18 Binding Protein

Summary for 7AL7

• Entry DOI: 10.2210/pdb7al7/pdb
• Descriptor: Interleukin-18-binding protein, Glutathione S-transferase class-mu 26 kDa isozyme,Interleukin-18, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (4 entities in total)
• Functional Keywords: cytokine, decoy receptor, antagonist, complex
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 65108.75

Authors

Detry, S.,Andries, J.,Bloch, Y.,Clancy, D.,Savvides, S.N. (deposition date: 2020-10-05, release date: 2022-04-20, Last modification date: 2024-10-16)

Primary citation

Detry, S.,Andries, J.,Bloch, Y.,Gabay, C.,Clancy, D.M.,Savvides, S.N.
Structural basis of human IL-18 sequestration by the decoy receptor IL-18 binding protein in inflammation and tumor immunity.
J.Biol.Chem., 298:101908-101908, 2022

PubMed Abstract: Human Interleukin-18 (IL-18) is an omnipresent proinflammatory cytokine of the IL-1 family with central roles in autoimmune and inflammatory diseases and serves as a staple biomarker in the evaluation of inflammation in physiology and disease, including the inflammatory phase of COVID-19. The sequestration of IL-18 by its soluble decoy receptor IL-18-Binding Protein (IL-18BP) is critical to the regulation of IL-18 activity. Since an imbalance in expression and circulating levels of IL-18 is associated with disease, structural insights into how IL-18BP outcompetes binding of IL-18 by its cognate cell-surface receptors are highly desirable; however, the structure of human IL-18BP in complex with IL-18 has been elusive. Here, we elucidate the sequestration mechanism of human IL-18 mediated by IL-18BP based on the crystal structure of the IL-18:IL-18BP complex. These detailed structural snapshots reveal the interaction landscape leading to the ultra-high affinity of IL-18BP toward IL-18 and identify substantial differences with respect to previously characterized complexes of IL-18 with IL-18BP of viral origin. Furthermore, our structure captured a fortuitous higher-order assembly between IL-18 and IL-18BP coordinated by a disulfide-bond distal to the binding surface connecting IL-18 and IL-18BP molecules from different complexes, resulting in a novel tetramer with 2:2 stoichiometry. This tetrapartite assembly was found to restrain IL-18 activity more effectively than the canonical 1:1 complex. Collectively, our findings provide a framework for innovative, structure-driven therapeutic strategies and further functional interrogation of IL-18 in physiology and disease.

PubMed: 35398099
DOI: 10.1016/j.jbc.2022.101908

Experimental method

X-RAY DIFFRACTION (1.801 Å)