X-ray Crystal Structures of Short Antimicrobial Peptides as Pseudomonas aeruginosa Lectin B Complexes

Baeriswyl, Stéphane; Gan, Bee Ha; Siriwardena, Thissa N.; Visini, Ricardo; Robadey, Maurane; Javor, Sacha; Stocker, Achim; Darbre, Tamis; Reymond, Jean-Louis (2019). X-ray Crystal Structures of Short Antimicrobial Peptides as Pseudomonas aeruginosa Lectin B Complexes. ACS Chemical Biology, 14(4), pp. 758-766. American Chemical Society 10.1021/acschembio.9b00047

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Herein, we report X-ray crystal structures of 11–13 residue antimicrobial peptides (AMPs) active against Pseudomonas aeruginosa as complexes of fucosylated d-enantiomeric sequences with the P. aeruginosa lectin LecB. These represent the first crystal structures of short AMPs. In 24 individual structures of eight different peptides, we found mostly α-helices assembled as two-helix or four-helix bundles with a hydrophobic core and cationic residues pointing outside. Two of the analogs formed an extended structure engaging in multiple contacts with the lectin. Molecular dynamics (MD) simulations showed that α-helices are stabilized by bundle formation and suggested that the N-terminal acyl group present in the linker to the fucosyl group can extend the helix by one additional H-bond and increase α-helix amphiphilicity. Investigating N-terminal acylation led to AMPs with equivalent and partly stronger antibacterial effects compared to the free peptide.

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