Rational design of a receptor super-antagonist of human interleukin-6

R. Savino, L. Ciapponi, A. Lahm, A. Demartis, A. Cabibbo, C. Toniatti, P. Delmastro, S. Altamura, G. Ciliberto

Research output: Contribution to journalArticle

Abstract

Interleukin-6 (IL-6) is a differentiation and growth factor for a variety of cell types and its excessive production plays a major role in the pathogenesis of multiple myeloma and post-menopausal osteoporosis. IL-6, a four-helix bundle cytokine, is believed to interact sequentially with two transmembrane receptors, the low-affinity IL-6 receptor (IL-6Rα) and the signal transducer gp130, via distinct binding sites. In this paper we show that combined mutations in the predicted A and C helices, previously suggested to establish contacts with gp130, give rise to variants with no bioactivity but unimpaired binding to IL-6Rα. These mutants behave as full and selective IL-6 receptor antagonists on a variety of human cell lines. Furthermore, a bifacial mutant was generated (called IL-6 super-antagonist) in which the antagonist mutations were combined with amino acid substitutions in the predicted D helix that increase binding for IL-6Rα. The IL-6 super-antagonist has no bioactivity, but improved first receptor occupancy and, therefore, fully inhibits the wild-type cytokine at low dosage. The demonstration of functionally independent receptor binding sites on IL-6 suggests that it could be possible to design super-antagonists of other helical cytokines which drive the assembly of structurally related multisubunit receptor complexes.

Original languageEnglish
Pages (from-to)5863-5870
Number of pages8
JournalEMBO Journal
Volume13
Issue number24
Publication statusPublished - 1994

Keywords

  • Antagonist
  • Interleukin-6
  • Multiple
  • Myeloma
  • Receptor

ASJC Scopus subject areas

  • Cell Biology
  • Genetics

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    Savino, R., Ciapponi, L., Lahm, A., Demartis, A., Cabibbo, A., Toniatti, C., Delmastro, P., Altamura, S., & Ciliberto, G. (1994). Rational design of a receptor super-antagonist of human interleukin-6. EMBO Journal, 13(24), 5863-5870.