A new cytokine-receptor binding mode revealed by the crystal structure of the IL-1 receptor with an antagonist

Herman Schreuder, Chantal Tardif, Susanne Trump-Kallmeyer, Adolfo Soffientini, Edoardo Sarubbi, Ann Akeson, Terry Bowlin, Stephen Yanofsky and Ronald W. Barrett
Additional contact information
Herman Schreuder: Marion Merrell Dow Research Institute
Chantal Tardif: Marion Merrell Dow Research Institute
Susanne Trump-Kallmeyer: Marion Merrell Dow Research Institute
Adolfo Soffientini: Lepetit Research Centre
Edoardo Sarubbi: Lepetit Research Centre
Ann Akeson: Hoechst Marion Roussel Inc.
Terry Bowlin: Lepetit Research Centre
Stephen Yanofsky: Affymax
Ronald W. Barrett: Affymax

Nature, 1997, vol. 386, issue 6621, 194-200

Abstract: 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.

Date: 1997
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DOI: 10.1038/386194a0

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