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

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
Enheter & grupper
Externa organisationer
  • Nanyang Technological University
  • Agency for Science, Technology and Research: Bioinformatics Institute (A*STAR BII)
  • Uppsala universitet
  • Aarhus University
  • National University of Singapore
  • University of Copenhagen
  • Lee Kong Chian School of Medicine
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Biofysik
Originalspråkengelska
Artikelnummer2762
TidskriftNature Communications
Volym9
Utgåva nummer1
StatusPublished - 2018 jul 17
PublikationskategoriForskning
Peer review utfördJa