Abstract
Treatment of Gram-negative bacterial infections with antimicrobial agents can cause release of the endotoxin lipopolysaccharide (LPS), the potent initiator of sepsis, which is the major cause of mortality in intensive care units worldwide. Structural information on peptides bound to LPS can lead to the development of more effective endotoxin neutralizers. Short linear antimicrobial and endotoxin-neutralizing peptide LF11, based on the human lactoferrin, binds to LPS, inducing a peptide fold with a "T-shaped" arrangement of a hydrophobic core and two clusters of basic residues that match the distance between the two phosphate groups of LPS. Side chain arrangement of LF11 bound to LPS extends the previously proposed LPS binding pattern, emphasizing the importance of both electrostatic and hydrophobic interactions in a defined geometric arrangement. In anionic micelles, the LF11 forms amphipathic conformation with a smaller hydrophobic core than in LPS, whereas in zwitterionic micelles, the structure is even less defined. Protection of tryptophan fluorescence quenching in the order SDS>LPS>DPC and hydrogen exchange protection indicates the decreasing extent of insertion of the N terminus and potential role of peptide plasticity in differentiation between bacterial and eukaryotic membranes.
Highlights
Bacterial lipopolysaccharide (LPS)1 is one of the most potent inducers of the innate immune response
We have compared the structure of the LF11-LPS complex with the FhuA-LPS complex (Protein Data Bank code 1QFF), the only determined protein structure with bound LPS, where the membrane protein FhuA interacts with LPS via the side chains of residues from three antiparallel  strands [6]
Despite a completely different backbone fold, the side chains of LF11 interacting with LPS correspond quite well to those of FhuA when the LPS molecules of both complexes are superimposed (Fig. 6), i.e. Arg5 of LF11 corresponds to Lys439 of FhuA, Lys9 to Lys351, Arg11 to Lys351, and Phe1 to Phe355, respectively, with a side chain r.m.s.d. of 2.8 Å
Summary
Bacterial lipopolysaccharide (LPS) is one of the most potent inducers of the innate immune response. The only precise structural information of LPS interacting with a protein originates from the crystal structure of the Escherichia coli iron uptake receptor protein FhuA, which is an integral membrane protein and has been fortuitously crystallized in complex with an LPS molecule [6]. Based on this complex, a three-dimensional structural pattern has been proposed consisting of the geometric arrangement of cationic side chains, to which many of the proteins known to interact with LPS adhere [7]. Attempts to determine the structure of lactoferricin or any other LPS-neutralizing peptide of eukaryotic origin in complex with LPS have not been successful
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