Rational design of a GCN4-derived mimetic of interleukin-4.
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-4R alpha). 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-4R alpha was transferred in a stepwise manner, using computer-aided molecular modeling. The resulting molecules bind IL-4R alpha with affinities ranging from 2 mM to 5 microM, 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.
Domingues
H
H
European Molecular Biology Laboratory, Heidelberg, Germany.
Cregut
D
D
Sebald
W
W
Oschkinat
H
H
Serrano
L
L
D000595:Amino Acid Sequence; D004268:DNA-Binding Proteins; D015195:Drug Design; D005656:Fungal Proteins / Q000138:chemical synthesis / Q000737:chemistry*; D015847:Interleukin-4 / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D011494:Protein Kinases / Q000138:chemical synthesis / Q000737:chemistry*; D017433:Protein Structure, Secondary; D019948:Receptors, Interleukin-4 / Q000737:chemistry*; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D013696:Temperature; D013816:Thermodynamics
D004268:DNA-Binding Proteins; D005656:Fungal Proteins; D019948:Receptors, Interleukin-4; D029701:Saccharomyces cerevisiae Proteins; D015847:Interleukin-4; D011494:Protein Kinases