4P0L

Crystal Structure of Double Loop-Swapped Interleukin-36Ra With Additional Point Mutations

Summary for 4P0L

• Entry DOI: 10.2210/pdb4p0l/pdb
• Related: 4P0J 4P0K
• Descriptor: Interleukin-36 receptor antagonist/Interleukin-36 gamma chimera protein (2 entities in total)
• Functional Keywords: chimera protein, interleukin, cytokine
• Biological source: Homo sapiens (Human)
• Cellular location: Secreted: Q9UBH0
• Total number of polymer chains: 1
• Total formula weight: 16768.97

Authors

Guenther, S.,Sundberg, E.J. (deposition date: 2014-02-21, release date: 2014-06-25, Last modification date: 2023-09-27)

Primary citation

Gunther, S.,Sundberg, E.J.
Molecular Determinants of Agonist and Antagonist Signaling through the IL-36 Receptor.
J Immunol., 193:921-930, 2014

PubMed Abstract: The IL-1 family consists of 11 cytokines that control a complex network of proinflammatory signals critical for regulating immune responses to infections. They also play a central role in numerous chronic inflammatory disorders. Accordingly, inhibiting the activities of these cytokines is an important therapeutic strategy for treating autoimmune diseases and lymphomas. Agonist cytokines in the IL-1 family activate signaling by binding their cognate receptor and then recruiting a receptor accessory protein. Conversely, antagonist cytokines bind their cognate receptor but prohibit recruitment of receptor accessory protein, which precludes functional signaling complexes. The IL-36 subfamily of cytokines is the most diverse, including three agonists and at least one antagonist, and is the least well-characterized group within this family. Signaling through the IL-36 receptor directly stimulates dendritic cells and primes naive CD4 T cells for Th1 responses. Appropriately balanced IL-36 signaling is a critical determinant of skin and lung health. IL-36 signaling has been presumed to function analogously to IL-1 signaling. In this study, we have defined molecular determinants of agonist and antagonist signaling through the IL-36 receptor. We present the crystal structure of IL-36γ, which, to our knowledge, is the first reported structure of an IL-36 agonist. Using this structure as a guide, we designed a comprehensive series of IL-36 agonist/antagonist chimeric proteins for which we measured binding to the IL-36 receptor/IL-1 receptor accessory protein complex and functional activation and inhibition of signaling. Our data reveal how the fine specificity of IL-36 signaling is distinct from that of IL-1.

PubMed: 24935927
DOI: 10.4049/jimmunol.1400538

Experimental method

X-RAY DIFFRACTION (1.55 Å)