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

Author

Listed:
  • Rathi Saravanan

    (Nanyang Technological University)

  • Daniel A Holdbrook

    (Bioinformatics Institute (A*STAR))

  • Jitka Petrlova

    (Lund University)

  • Shalini Singh

    (Uppsala University)

  • Nils A Berglund

    (Bioinformatics Institute (A*STAR)
    Aarhus University)

  • Yeu Khai Choong

    (Nanyang Technological University)

  • Sven Kjellström

    (Lund University)

  • Peter J Bond

    (Bioinformatics Institute (A*STAR)
    National University of Singapore)

  • Martin Malmsten

    (Uppsala University
    University of Copenhagen)

  • Artur Schmidtchen

    (Nanyang Technological University
    Lund University
    University of Copenhagen)

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.

Suggested Citation

  • Rathi Saravanan & Daniel A Holdbrook & Jitka Petrlova & Shalini Singh & Nils A Berglund & Yeu Khai Choong & Sven Kjellström & Peter J Bond & Martin Malmsten & Artur Schmidtchen, 2018. "Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05242-0
    DOI: 10.1038/s41467-018-05242-0
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    Cited by:

    1. Ganna Petruk & Manoj Puthia & Firdaus Samsudin & Jitka Petrlova & Franziska Olm & Margareta Mittendorfer & Snejana Hyllén & Dag Edström & Ann-Charlotte Strömdahl & Carl Diehl & Simon Ekström & Björn W, 2023. "Targeting Toll-like receptor-driven systemic inflammation by engineering an innate structural fold into drugs," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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