A NEW CYTOKINE-RECEPTOR BINDING MODE REVEALED BY THE CRYSTAL-STRUCTURE OF THE IL-1 RECEPTOR WITH AN ANTAGONIST

Inflammation, regardless of whether it is provoked by infection or by tissue damage, starts with the activation of macrophages which initiat e a cascade of inflammatory responses by producing the cytokines inter leukin-1 (IL-1) and tumour necrosis factor-alpha (ref. 1). Three natur ally occurring ligands for the IL-1 receptor (IL1R) exist: the agonist s IL-1 alpha and IL-1 beta and the IL-1-receptor antagonist IL1RA. (re f. 2). IL-1 is the only cytokine for which a naturally occurring antag onist is known. Here we describe the crystal structure at 2.7 Angstrom resolution of the soluble extracellular part of type-I IL1R complexed with IL1RA. The receptor consists of three immunoglobulin-like domain s. Domains 1 and 2 are tightly - linked, but domain three is completel y separate and connected by a flexible linker. Residues of all three d omains contact the antagonist and include the five critical IL1RA resi dues which were identified by site-directed mutagenesis(3). A region t hat is important for biological function in IL-1 beta, the 'receptor t rigger site' is not in direct contact with the receptor in the IL1RA c omplex. Modelling studies suggest that this IL-1 beta trigger site mig ht induce a movement of domain 3.