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Rational design of a GCN4-derived mimetic of interleukin-4

Nature Structural Biology volume 6, pages 652–656 (1999)Cite this article

Abstract

In this work we describe the rational design of two helix coiled coil peptide mimetics of interleukin-4 (IL-4) which are able to recognize and bind its high affinity receptor (IL-4Rα). We have used the leucine-zipper domain of the yeast transcription factor GCN4 as a scaffold into which the putative binding epitope of IL-4 for IL-4Rα was transferred in a stepwise manner, using computer-aided molecular modeling. The resulting molecules bind IL-4Rα with affinities ranging from 2 mM to 5 μM, depending on the fraction of the IL-4 binding site incorporated and on their stability. To our knowledge this is the first time a molecule capable of binding a cytokine receptor has been successfully designed in a rational manner.

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Figure 1: Superimposition of the GCN4 coiled coil (red) on helices A and C of IL-4 (yellow).
Figure 2: a, Thermal denaturation of MAR-IL4 (squares), 12CMAR-IL4 (triangles) and 26CMAR-IL4 (circles).
Figure 3: a, Stereo view of the superimposition of the energy-minimized model of 12CMAR-IL4 (orange) on helix A and C of IL-4 (grey), showing the side chains involved in binding to IL-4Rα (Lys 7, Arg 11, Lys 14, Arg 15, Arg 18, Glu 20, Trp 21, Ile 24).
Figure 4: Correlation between the binding free energies determined for the different peptides (ΔG) and the expected changes in binding free energy in IL-4 from experimental mutagenesis data11.

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Notes

  1. Note:

    As a result of an error in production, the print version of this paper is missing references 28-30. The full-text and PDF versions presented here on the web site include those references. We regret any confusion this may have caused.

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Acknowledgements

We are very greatful to A. Pastore and V. Saudek for providing us with NMR data on GCN4. This work is protected under an international patent application No. PCT/EP98/07286

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Authors and Affiliations

  1. European Molecular Biology Laboratory, Meyerhofstrasse 1, Heidelberg, D-69012, Germany

    Helena Domingues, David Cregut & Luis Serrano

  2. Theodor-Boveri Institut für Biowissenschaft (Biozentrum), Physiologische Chemie II, Am Hubland, Würzburg, D-97074, Germany

    Walter Sebald

  3. Forschungsinstitut für Molekulare Pharmakologie, Alfred-Kowalkestrasse 4, 10315 Berlin, Germany

    Hartmut Oschkinat

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  1. Helena Domingues
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Correspondence to Hartmut Oschkinat or Luis Serrano.

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Domingues, H., Cregut, D., Sebald, W. et al. Rational design of a GCN4-derived mimetic of interleukin-4. Nat Struct Mol Biol 6, 652–656 (1999). https://doi.org/10.1038/10706

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