Abstract
Inflammation, regardless of whether it is provoked by infection or by tissue damage, starts with the activation of macrophages which initiate a cascade of inflammatory responses by producing the cytokines interleukin-1 (IL-1) and tumour necrosis factor-α (ref. 1). Three naturally occurring ligands for the IL-1 receptor (IL1R) exist: the agonists IL-1α and IL-lβ and the IL-1-receptor antagonist IL1RA (ref. 2). IL-1 is the only cytokine for which a naturally occurring antagonist is known. Here we describe the crystal structure at 2.7 Å resolution of the soluble extracellular part of type-I IL1R complexed with IL1RA. The receptor consists of three immunoglobulin-like domains. Domains 1 and 2 are tightly linked, but domain three is completely separate and connected by a flexible linker. Residues of all three domains contact the antagonist and include the five critical IL1RA residues which were identified by site-directed mutagenesis3. A region that is important for biological function in IL-1β, the 'receptor trigger site', is not in direct contact with the receptor in the IL1RA complex. Modelling studies suggest that this IL-1β trigger site might induce a movement of domain 3.
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Schreuder, H., Tardif, C., Trump-Kallmeyer, S. et al. A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist. Nature 386, 194–200 (1997). https://doi.org/10.1038/386194a0
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DOI: https://doi.org/10.1038/386194a0
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