Abstract
BackgroundBioactive cyclic peptides derived from natural sources are well studied, particularly those derived from non-ribosomal synthetases in fungi or bacteria. Ribosomally synthesised bioactive disulphide-bonded loops represent a large, naturally enriched library of potential bioactive compounds, worthy of systematic investigation.ResultsWe examined the distribution of short cyclic loops on the surface of a large number of proteins, especially membrane or extracellular proteins. Available three-dimensional structures highlighted a number of disulphide-bonded loops responsible for the majority of the likely binding interactions in a variety of protein complexes, due to their location at protein-protein interfaces. We find that disulphide-bonded loops at protein-protein interfaces may, but do not necessarily, show biological activity independent of their parent protein. Examining the conservation of short disulphide bonded loops in proteins, we find a small but significant increase in conservation inside these loops compared to surrounding residues. We identify a subset of these loops that exhibit a high relative conservation, particularly among peptide hormones.ConclusionsWe conclude that short disulphide-bonded loops are found in a wide variety of biological interactions. They may retain biological activity outside their parent proteins. Such structurally independent peptides may be useful as biologically active templates for the development of novel modulators of protein-protein interactions.Electronic supplementary materialThe online version of this article (doi:10.1186/1471-2105-15-305) contains supplementary material, which is available to authorized users.
Highlights
Bioactive cyclic peptides derived from natural sources are well studied, those derived from non-ribosomal synthetases in fungi or bacteria
Finding disulphide-bonded loops at protein-protein interfaces To identify short disulphide bonded loops that play a crucial role at Protein-Protein Interfaces, we set out to find known three-dimensional structures of protein complexes mediated by a disulphide bonded loops
2,380 Protein Data Bank (PDB) structures [21] corresponding to Uniprot entries with annotated short disulphide-bonded loops were downloaded. (Figure 1(a)) Disulphide-bonded loops at protein surfaces or interfaces were identified as described in the Methods
Summary
Bioactive cyclic peptides derived from natural sources are well studied, those derived from non-ribosomal synthetases in fungi or bacteria. Cyclic peptides are macrocyclic peptides which possess where linear peptide side chains or termini are covalently bonded to shape the peptide into a ring. Macrocyclic compounds such as cyclic peptides have been a renewed focus of drug discovery in recent years [1], and identifying a biologically pre-designed set of cyclic peptides in protein sequences would be of great potential interest in pharmaceutical development. Cyclic peptides are interesting from a drug development point of view, due to their generally better specificity, proteolytic resistance, and stability than linear peptides [4]. This work use the term “small macrocyclic peptides” to refer to cyclic peptides in general, including the disulphide-cyclised peptides described in this work
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