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

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 transmem...

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Bibliographic Details
Published in:The EMBO journal 1994-12, Vol.13 (24), p.5863-5870
Main Authors: Savino, R., Ciapponi, L., Lahm, A., Demartis, A., Cabibbo, A., Toniatti, C., Delmastro, P., Altamura, S., Ciliberto, G.
Format: Article
Language:English
Subjects:
Carcinoma, Hepatocellular - metabolism
Dose-Response Relationship, Drug
Drug Design
Humans
Interleukin-6 - analogs & derivatives
Interleukin-6 - genetics
Interleukin-6 - pharmacology
Liver Neoplasms - metabolism
Models, Molecular
Multiple Myeloma - metabolism
Mutagenesis, Site-Directed
Protein Structure, Secondary
Receptors, Interleukin - antagonists & inhibitors
Receptors, Interleukin-6
Sensitivity and Specificity
Tumor Cells, Cultured
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Summary: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‐6R alpha) 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‐6R alpha. 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‐6R alpha. 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.
ISSN:0261-4189
1460-2075
DOI:10.1002/j.1460-2075.1994.tb06931.x