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Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides.


ABSTRACT: Thrombin-derived C-terminal peptides (TCPs) of about 2?kDa are present in wounds, where they exert anti-endotoxic functions. Employing a combination of nuclear magnetic resonance spectroscopy (NMR), biophysical, mass spectrometry and cellular studies combined with in silico multiscale modelling, we here determine the bound conformation of HVF18 (HVFRLKKWIQKVIDQFGE), a TCP generated by neutrophil elastase, in complex with bacterial lipopolysaccharide (LPS) and define a previously undisclosed interaction between TCPs and human CD14. Further, we show that TCPs bind to the LPS-binding hydrophobic pocket of CD14 and identify the peptide region crucial for TCP interaction with LPS and CD14. Taken together, our results demonstrate the role of structural transitions in LPS complex formation and CD14 interaction, providing a molecular explanation for the previously observed therapeutic effects of TCPs in experimental models of bacterial sepsis and endotoxin shock.

SUBMITTER: Saravanan R 

PROVIDER: S-EPMC6050251 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides.

Saravanan Rathi R   Holdbrook Daniel A DA   Petrlova Jitka J   Singh Shalini S   Berglund Nils A NA   Choong Yeu Khai YK   Kjellström Sven S   Bond Peter J PJ   Malmsten Martin M   Schmidtchen Artur A  

Nature communications 20180717 1


Thrombin-derived C-terminal peptides (TCPs) of about 2 kDa are present in wounds, where they exert anti-endotoxic functions. Employing a combination of nuclear magnetic resonance spectroscopy (NMR), biophysical, mass spectrometry and cellular studies combined with in silico multiscale modelling, we here determine the bound conformation of HVF18 (HVFRLKKWIQKVIDQFGE), a TCP generated by neutrophil elastase, in complex with bacterial lipopolysaccharide (LPS) and define a previously undisclosed inte  ...[more]

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