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文献データベース
| Authors: |
L. Kang, K. Bondensgaard, T. Li, R. Hartmann and S. A. Hjorth |
| Year: |
2010 |
| Journal: |
J Biol Chem |
| Volume: |
285 |
| Pages: |
12223-31 Epub 2010 Feb 18 |
| Title: |
Rational design of interleukin-21 antagonist through selective elimination of the gammaC binding epitope |
| Abstract: |
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. |
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Alfred G. Smith という著者を検索する場合には、「Smith」または「Smith, A.G」と入力してください。 その他
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