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

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  • Rathi Saravanan
  • Daniel A Holdbrook
  • Jitka Petrlova
  • Shalini Singh
  • Nils A Berglund
  • Yeu Khai Choong
  • Sven Kjellström
  • Peter J Bond
  • Martin Malmsten
  • Artur Schmidtchen
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftNature Communications
Vol/bind9
Udgave nummer1
Sider (fra-til)2762
ISSN2041-1723
DOI
StatusUdgivet - 17 jul. 2018

ID: 56331444