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

124 Citations (Scopus)

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

Fingerprint

Interleukin-6 Receptors
Interleukin-6
Cytokines
Bioactivity
Cytokine Receptor gp130
Binding Sites
Growth Differentiation Factors
Mutation
Postmenopausal Osteoporosis
Amino Acid Substitution
Multiple Myeloma
Substitution reactions
Demonstrations
Cells
Amino Acids
Cell Line

Keywords

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

ASJC Scopus subject areas

  • Cell Biology
  • Genetics

Cite this

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

Rational design of a receptor super-antagonist of human interleukin-6. / Savino, R.; Ciapponi, L.; Lahm, A.; Demartis, A.; Cabibbo, A.; Toniatti, C.; Delmastro, P.; Altamura, S.; Ciliberto, G.

In: EMBO Journal, Vol. 13, No. 24, 1994, p. 5863-5870.

Research output: Contribution to journalArticle

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, vol. 13, no. 24, pp. 5863-5870.
Savino R, Ciapponi L, Lahm A, Demartis A, Cabibbo A, Toniatti C et al. Rational design of a receptor super-antagonist of human interleukin-6. EMBO Journal. 1994;13(24):5863-5870.
Savino, R. ; Ciapponi, L. ; Lahm, A. ; Demartis, A. ; Cabibbo, A. ; Toniatti, C. ; Delmastro, P. ; Altamura, S. ; Ciliberto, G. / Rational design of a receptor super-antagonist of human interleukin-6. In: EMBO Journal. 1994 ; Vol. 13, No. 24. pp. 5863-5870.
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