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Rational design of interleukin-21 antagonist through selective elimination of the gammaC binding epitope

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  • Lishan Kang
  • ,
  • Kent Bondensgaard
  • ,
  • Tengkun Li
  • ,
  • Rune Hartmann
  • Siv A Hjorth, Denmark
  • Department of Medical Microbiology and Immunology
  • Department of Molecular Biology
The cytokine interleukin (IL)-21 exerts pleiotropic effects acting through innate as well as adaptive immune responses. The activities of IL-21 are mediated through binding to its cognate receptor complex composed of the IL-21 receptor private chain (IL-21Ralpha) and the common gamma-chain (gammaC), the latter being shared by IL-2, IL-4, IL-7, IL-9, and IL-15. The binding energy of the IL-21 ternary complex is predominantly provided by the high affinity interaction between IL-21 and IL-21Ralpha, whereas the interaction between IL-21 and gammaC, albeit essential for signaling, is rather weak. The design of IL-21 analogues, which have lost most or all affinity toward the signaling gammaC chain, while simultaneously maintaining a tight interaction with the private chain, would in theory represent candidates for IL-21 antagonists. We predicted the IL-21 residues, which compose the gammaC binding epitope using homology modeling and alignment with the related cytokines, IL-2 and IL-4. Next we systematically analyzed the predicted binding epitope by a mutagenesis study. Indeed two mutants, which have significantly impaired gammaC affinity with undiminished IL-21Ralpha affinity, were successfully identified. Functional studies confirmed that these two novel hIL-21 double mutants do act as hIL-21 antagonists.
Original languageEnglish
JournalJournal of Biological Chemistry
Volume285
Issue16
Pages (from-to)12223-31
Number of pages9
ISSN0021-9258
DOIs
Publication statusPublished - 16 Apr 2010

    Research areas

  • Amino Acid Sequence, Amino Acid Substitution, Binding Sites, Cell Line, Drug Design, Epitopes, Humans, Interleukin-2, Interleukin-4, Interleukins, Models, Molecular, Molecular Sequence Data, Multiprotein Complexes, Mutagenesis, Site-Directed, Protein Interaction Domains and Motifs, Receptors, Interleukin-21, Recombinant Proteins, Sequence Homology, Amino Acid, Structural Homology, Protein

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