1qx9
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Structure of a cyclic indolicidin peptide derivative with higher charge
OverviewOverview
Indolicidin is an antimicrobial cationic peptide with broad-spectrum, activity isolated from bovine neutrophils. An indolicidin analogue CP-11, ILKKWPWWPWRRK-NH(2), with improved activity against Gram-negative bacteria, had increased positive charge and amphipathicity while maintaining the, short length of the parent molecule. The structure of CP-11 in the, presence of dodecylphosphocholine (DPC) micelles was determined using, nuclear magnetic resonance spectroscopy. CP-11 was found to be an, amphipathic molecule with a U-shaped backbone bringing the N- and, C-termini in close proximity. On the basis of this close proximity, a, cyclic disulfide-bonded peptide cycloCP-11, ICLKKWPWWPWRRCK-NH(2), was, designed to stabilize the lipid-bound structure and to increase protease, resistance. The three-dimensional structure of cycloCP-11 was determined, under the same conditions as for the linear peptide and was found to be, similar to CP-11. Both CP-11 and cycloCP-11 associated with phospholipid, membranes in a similar manner as indicated by circular dichroism and, fluorescence spectra. The minimal inhibitory concentrations of CP-11 and, cycloCP-11 for a range of bacteria differed by no more than 2-fold, and, they were nonhemolytic at concentrations up to 256 microg/mL. Cyclization, was found to greatly increase protease stability. The half-life of, cycloCP-11 in the presence of trypsin was increased by 4.5-fold from 4 to, 18 min. More importantly, the antibacterial activity of cycloCP-11, but, not that of CP-11, in the presence of trypsin was completely retained up, to 90 min since the major degradation product was equally active. A, structural comparison of CP-11 and cycloCP-11 revealed that the higher, trypsin resistance of cycloCP-11 may be due to the more compact packing of, lysine and tryptophan side chains. These findings suggest that cyclization, may serve as an important strategy in the rational design of antimicrobial, peptides.
About this StructureAbout this Structure
1QX9 is a Single protein structure of sequence from [1] with NH2 as ligand. Full crystallographic information is available from OCA.
ReferenceReference
Structure-based design of an indolicidin peptide analogue with increased protease stability., Rozek A, Powers JP, Friedrich CL, Hancock RE, Biochemistry. 2003 Dec 9;42(48):14130-8. PMID:14640680
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