1.9 Acrystal structure of interleukin 6: implications for a novel mode of receptor dimerization and signaling

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Abstract
Interleukin 6 (IL‐6) has many biological activities in vivo , and deregulation has been implicated in many disease processes. IL‐6, a 185 amino acid polypeptide was refolded, purified and crystallized. The crystals diffracted to beyond 1.9 Å and the structure was solved using single isomorphous replacement. The X‐ray structure of IL‐6 is composed of a four helix bundle linked by loops and an additional mini‐helix. 157 out of 185 residues are well defined in the final structure, with 18 N‐terminal and 8 A–B loop amino acids displaying no interpretable electron density. The three‐dimensional structure has been used to construct a model of IL‐6 interacting with the IL‐6 receptor (α‐chain) and gp130 (β‐chain) that gives new insight into the process of molecular recognition and signaling. Based on this model, we predict a fourth binding site on IL‐6, a low affinity IL‐6–IL‐6 interaction, which may be necessary for the sequential assembly of a functional hexameric IL‐6 receptor complex.