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

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Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides. / Saravanan, Rathi; Holdbrook, Daniel A.; Petrlova, Jitka; Singh, Shalini; Berglund, Nils A.; Choong, Yeu Khai; Kjellström, Sven; Bond, Peter J.; Malmsten, Martin; Schmidtchen, Artur.

In: Nature Communications, Vol. 9, No. 1, 2762, 17.07.2018.

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Saravanan, Rathi ; Holdbrook, Daniel A. ; Petrlova, Jitka ; Singh, Shalini ; Berglund, Nils A. ; Choong, Yeu Khai ; Kjellström, Sven ; Bond, Peter J. ; Malmsten, Martin ; Schmidtchen, Artur. / Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides. In: Nature Communications. 2018 ; Vol. 9, No. 1.

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TY - JOUR

T1 - Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides

AU - Saravanan, Rathi

AU - Holdbrook, Daniel A.

AU - Petrlova, Jitka

AU - Singh, Shalini

AU - Berglund, Nils A.

AU - Choong, Yeu Khai

AU - Kjellström, Sven

AU - Bond, Peter J.

AU - Malmsten, Martin

AU - Schmidtchen, Artur

PY - 2018/7/17

Y1 - 2018/7/17

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-018-05242-0

DO - 10.1038/s41467-018-05242-0

M3 - Article

VL - 9

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 2762

ER -