SOLUTION STRUCTURE OF RECOMBINANT HUMAN INTERLEUKIN-6

Interleukin-6 (IL-6) is a 185 amino-acid cytokine which exerts multipl e biological effects in vivo and whose dysregulation underlies several disease processes The solution structure of recombinant human interle ukin-6 has now been determined using heteronuclear three and four-dime nsional NMR spectroscopy. The structure of the molecule was determined using 3044 distance and torsion restraints derived by NMR spectroscop y to generate an ensemble of 32 structures using a combined distance g eometry/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 An gstrom in any of the final 32 structures and the ensemble has an avera ge-to-the-mean backbone root-mean-square deviation of 0.50 Angstrom fo r the core four-helix bundle. Although the amino-terminal 19 amino aci ds are disordered in solution, the remainder of the molecule has a wel l defined structure that shares many features displayed by other long- chain four-helix bundle cytokines. The high-resolution NMR structure o f hIL-6 is used to rationalize available mutagenesis data in terms of a heteromeric receptor complex. (C) 1997 Academic Press Limited.