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Generation of interleukin-6 receptor antagonists by molecular-modeling guided mutagenesis of residues important for gp130 activation
- Source :
- Scopus-Elsevier, Europe PubMed Central
- Publication Year :
- 1994
- Publisher :
- Wiley, 1994.
-
Abstract
- Interleukin-6 (IL-6) drives the sequential assembly of a receptor complex formed by the IL-6 receptor (IL-6R alpha) and the signal transducing subunit, gp130. A model of human IL-6 (hIL-6) was constructed by homology using the structure of bovine granulocyte colony stimulating factor. The modeled cytokine was predicted to interact sequentially with the cytokine binding domains of IL-6R alpha and gp130 bridging them in a way similar to that of the interaction between growth hormone and its homodimeric receptor. Several residues on helices A and C which were predicted as contact points between IL-6 and gp130 and therefore essential for IL-6 signal transduction, were subjected to site-directed mutagenesis individually or in combined form. Interestingly, while single amino acid changes never produced major alterations in IL-6 bioactivity, a subset of double mutants of Y31 and G35 showed a considerable reduction of biological activity and were selectively impaired from associating with gp130 in binding assays in vitro, while they maintained wild-type affinity towards hIL-6-R alpha. More importantly, we demonstrated the antagonistic effect of mutant Y31D/G35F versus wild-type IL-6.
- Subjects :
- Models, Molecular
Receptor complex
Molecular Sequence Data
Interleukin 5 receptor alpha subunit
CHO Cells
Interleukin-17 receptor
Biology
Crystallography, X-Ray
General Biochemistry, Genetics and Molecular Biology
Interleukin 10 receptor, alpha subunit
Antigens, CD
Cell surface receptor
Cricetinae
Granulocyte Colony-Stimulating Factor
Cytokine Receptor gp130
Tumor Cells, Cultured
Animals
Humans
Amino Acid Sequence
Cytokine binding
Molecular Biology
Genetics
Membrane Glycoproteins
General Immunology and Microbiology
Interleukin-6
General Neuroscience
Receptors, Interleukin
Glycoprotein 130
Receptors, Interleukin-6
Cell biology
Growth Hormone
Interleukin-6 receptor
Mutagenesis, Site-Directed
Cattle
Signal Transduction
Research Article
Subjects
Details
- ISSN :
- 02614189
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- The EMBO Journal
- Accession number :
- edsair.doi.dedup.....5f590f6f40c2b6835a1ea5f9877ac09a