REFINED CRYSTAL-STRUCTURE OF THE INTERLEUKIN-1 RECEPTOR ANTAGONIST - PRESENCE OF A DISULFIDE LINK AND A CIS-PROLINE

Interleukin-1 (IL-1) molecules an cytokines involved in the acute-phas e response against infection and injury. Three naturally occurring IL- 1 molecules are known, two agonists: IL-1 alpha and IL-1 beta, and one antagonist, the IL-1 receptor antagonist (IL-1ra). Although IL-1 acti on protects the organism by enhancing the response to pathogens, its o verproduction can lead to pathology and has been implicated in disease states that include septic shock, rheumatoid arthritis, graft versus host disease and certain leukemias. The crystal structure of IL-1ra ha s been solved at 0.21-nm resolution by molecular replacement using the IL-1 beta structure as a search model. The crystals contain two indep endent IL-1ra molecules which are very similar. IL-1ra has the same fo ld as IL-1 alpha and IL-1 beta The fold consists of twelve beta-strand s which form a six-stranded beta-barrel, closed on one side by three b eta-hairpin loops. Cys69 and Cys116 are linked via a disulfide bond an d Pro53 has been built in the cis-conformation. Comparison of the IL-1 ra structure with the IL-1 alpha and IL-1 beta structures present in t he Protein Data Bank shows that a putative receptor interaction region , involving the N-terminus up to the beginning of strand beta 1 and th e loops D and G, is very different in the three IL-1 molecules. Other putative interaction regions, as identified with mutagenesis studies, are structurally conserved and rigid, allowing precise and specific in teractions with the IL-1 receptor.