SOLUTION STRUCTURE OF SYNTHETIC PEPTIDES CORRESPONDING TO THE C-TERMINAL HELIX OF INTERLEUKIN-6

Two synthetic peptides corresponding to the C-terminal 19 residues of human and murine interleukin-6, respectively, have been synthesized an d their structures in solution investigated using high-resolution H-1- NMR spectroscopy. Both peptides show a marked dependence of chemical-s hift dispersion on pH, with a greater degree of structure apparent abo ve pH 4.5, where their glutamate carboxyl groups are ionised. In purel y aqueous solution, neither peptide adopts a well-defined structure, a lthough the murine peptide has characteristics of a nascent helix. Tit ration of the murine peptide with trifluoroethanol produced a signific ant increase in structure, which was then investigated using two-dimen sional NMR. In 50% (by vol.) trifluoroethanol the murine peptide consi sts of a well-defined central helix of 12 residues with unstructured N -terminal and C-terminal regions. These observations lend experimental support to the current model of the interleukin-6 structure, which pr oposes a four-helical bundle with the last helix encompassing the C-te rminal 20-30 residues. Furthermore, the fact that synthetic peptides c orresponding to part of the putative receptor-binding surface of inter leukin-6 are able to adopt a similar conformation in solution to that proposed for the intact protein suggests that such peptide analogues s hould be useful starting points in the design of peptide agonists and antagonists of interleukin-6.