2MQ5: Cysteine Deleted Protegrin-1 (CDP-1): Anti-bacterial Activity, Outer-Membrane Disruption and Selectivity

BACKGROUND: Protegin-1 (PG-1: RGGRLCYCRRRFCVCVGR-amide) assumes a rigid beta-hairpin like structure that is stabilized by two disulfide bridges between Cys6-Cys15 and Cys8-Cys13. Previous studies, employing linear analogs of PG-1, with Cys to Ala mutations or modified Cys, have demonstrated that the disulfide bridges are critical for the broad spectrum and salt resistant antimicrobial activity of PG-1. METHODS: In order to understand structural and functional roles of disulfide bonds in protegrins, we have synthesized a Cys deleted variant of PG-1 or CDP-1, RGGRLYRRRFVVGR-amide, and two of its analogs, RR11, RLYRRRFVVGR-amide, and LR10, LYRRRFVVGR-amide, containing deletion of residues at the N-terminus. These peptides have been characterized for bactericidal activity and mode of action in lipopolysaccharide (LPS) using optical spectroscopy, ITC and NMR. RESULTS: Antibacterial activity, against Gram-negative and Gram-positive strains, of the three peptides follows the order: CDP-1>RR11>LR10. LR10 displays only limited activity toward Gram-negative strains. CDP-1 demonstrates efficient membrane permeabilization and high-affinity interactions with LPS. CDP-1 and RR11 both assume beta-hairpin like compact structures in complex with LPS, whereas LR10 adopts an extended conformation in LPS. In zwitterionic DPC micelles CDP-1 and the truncated analog peptides do not adopt folded conformations. MAJOR CONCLUSIONS: Despite the absence of stabilizing disulfide bridges CDP-1 shows broad-spectrum antibacterial activity and assumes beta-hairpin like structure in complex with LPS. The beta-hairpin structure may be essential for outer membrane permeabilization and cell killing.
PDB ID: 2MQ5Download
MMDB ID: 121839
PDB Deposition Date: 2014/6/12
Updated in MMDB: 2014/08
Experimental Method:
solution nmr
Similar Structures:
Biological Unit for 2MQ5: monomeric; determined by author
Molecular Components in 2MQ5
Label Count Molecule
Protein (1 molecule)
Lr10 Peptide From Cysteine Deleted Protegrin-1
Molecule annotation
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Citing MMDB