Generation of highly stable IL-18 based on a ligand–receptor complex structure

Human interleukin-18 (hIL-18), initially cloned as an IFN-γ-inducing factor, has a key role in many inflammatory diseases. We have previously developed a high production system for correctly folded active hIL-18 protein, leading to the revelation of the 3D-structure and the receptor binding mode. Th...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2004-04, Vol.317 (1), p.181-186
Main Authors: Yamamoto, Yutaka, Kato, Zenichiro, Matsukuma, Eiji, Li, Ailian, Omoya, Kentaro, Hashimoto, Kazuyuki, Ohnishi, Hidenori, Kondo, Naomi
Format: Article
Language:English
Subjects:
3D-structure
Amino Acid Sequence
Amino Acid Substitution
Cysteine
Cysteine - chemistry
Cysteine - genetics
Dimerization
Drug Stability
Gene Expression - drug effects
Humans
IL-18
Interferon-gamma - biosynthesis
Interleukin-18 - biosynthesis
Interleukin-18 - chemistry
Interleukin-18 - genetics
Interleukin-18 - pharmacology
Interleukin-18 Receptor alpha Subunit
Ligands
Models, Molecular
Molecular Sequence Data
Mutant
Oxidation-Reduction
Protein Structure, Tertiary
Receptors, Interleukin - chemistry
Receptors, Interleukin-18
Recombinant Proteins - chemistry
Recombinant Proteins - genetics
Recombinant Proteins - pharmacology
Sequence Alignment
Stability
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Summary:Human interleukin-18 (hIL-18), initially cloned as an IFN-γ-inducing factor, has a key role in many inflammatory diseases. We have previously developed a high production system for correctly folded active hIL-18 protein, leading to the revelation of the 3D-structure and the receptor binding mode. These findings can strongly indicate the experimental and medical applications of IL-18; however, the recombinant protein is prone to be inactivated forming multimers. Recently, therapeutic approaches using recombinant IL-18 have shown the effectiveness for treatment of cancer; indicating the necessity of a more stable protein for therapy with intertrial reliability. Here we have generated a highly stable hIL-18 with replacement of cysteine by serine based on the tertiary structure and the binding mechanism, retaining the biological activity. Similar rational designs can be applied to develop new therapeutic molecules of other cytokines.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2004.03.024