Solution structure of recombinant human interleukin-6

Interleukin-6 (IL-6) is a 185 amino-acid cytokine which exerts multiple biological effects in vivo and whose dysregulation underlies several disease processes The solution structure of recombinant human interleukin-6 has now been determined using heteronuclear three and four-dimensional NMR spectroscopy. The structure of the molecule was determined using 3044 distance and torsion restraints derived by NMR spectroscopy to generate an ensemble of 32 structures using a combined distance geometry/simulated annealing protocol. The protein contains five alpha-helices interspersed with variable-length loops; four of these helices constitute a classical four-helix bundle with the fifth helix located in the CD loop. There were no distance violations greater than 0.3 Angstrom in any of the final 32 structures and the ensemble has an average-to-the-mean backbone root-mean-square deviation of 0.50 Angstrom for the core four-helix bundle. Although the amino-terminal 19 amino acids are disordered in solution, the remainder of the molecule has a well defined structure that shares many features displayed by other long-chain four-helix bundle cytokines. The high-resolution NMR structure of hIL-6 is used to rationalize available mutagenesis data in terms of a heteromeric receptor complex. (C) 1997 Academic Press Limited.