Analysis of Fish IL-1B and Derived Peptide Sequences Indicates Conserved Structures with Species-Specific IL-1 Receptor Binding: Implications for Pharmacological Design

Abstract : A large number of IL-1B protein sequences have become available recently from a range of vertebrate species and especially from bony fish. However, 3D structures are still only known for mammalian IL-1. In this review, we use a multiple sequence alignment of all published non-mammalian vertebrate IL-1B proteins to locate the structurally important residues critical for maintaining the B-trefoil fold and we investigate the degree to which functionally important residues involved in receptor binding are conserved across vertebrate species. We find that although there is a high level of variability of positions involved in receptor binding, the mode of binding and overall shape of the ligand-receptor complex is probably maintained. This implies that each species has evolved its own unique interleukin-1 signalling system through ligand-receptor co-evolution. Nonetheless, the IL-1B processing mechanism in non-mammalian vertebrates remains unclear because, with the exception of three bony fish, all non-mammalian IL-1B sequences discovered so far lack an ICE (Interleukin Converting Enzyme) cut site. The IL-1 system has become an important drug target because of its significance in inflammatory diseases. Research on peptides derived from IL-1B has identified peptides that possess agonist activity in humans and in trout, and peptides with antagonist activity. The agonist peptides map to two distinct loop regions of IL-1B that are known to interact with the flexible domain III of the corresponding receptor. Further analysis of the IL-1 system may prove useful in engineering IL-1 with improved features and in suggesting new avenues for therapeutic intervention.
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Current Pharmaceutical Design, Bentham Science Publishers, 2004, 10 (31), pp.3857-3871. 〈10.2174/1381612043382585〉
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Soumis le : samedi 21 novembre 2009 - 17:29:25
Dernière modification le : mardi 28 novembre 2017 - 15:18:03

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Antonis Koussounadis, David Ritchie, Graham Kemp, Christopher Secombes. Analysis of Fish IL-1B and Derived Peptide Sequences Indicates Conserved Structures with Species-Specific IL-1 Receptor Binding: Implications for Pharmacological Design. Current Pharmaceutical Design, Bentham Science Publishers, 2004, 10 (31), pp.3857-3871. 〈10.2174/1381612043382585〉. 〈inria-00434278〉

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