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

Antonis I. Koussounadis ; David W. Ritchie ; Graham J.L. Kemp (Institutionen för datavetenskap, Bioinformatik) ; Chris J. Secombes
Current Pharmaceutical Design (1381-6128). Vol. 10 (2004), 31, p. 3857-3871.
[Artikel, refereegranskad vetenskaplig]

A large number of IL-1 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-1beta proteins to locate the structurally important residues critical for maintaining the beta-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-1beta processing mechanism in non-mammalian vertebrates remains unclear because, with the exception of three bony fish, all non-mammalian IL-1beta 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-1beta 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-1beta 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.



Denna post skapades 2006-09-25. Senast ändrad 2015-11-20.
CPL Pubid: 2434

 

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Institutioner (Chalmers)

Institutionen för datavetenskap, Bioinformatik (2002-2004)

Ämnesområden

Industriell bioteknik

Chalmers infrastruktur