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

Nature Communications
Rathi SaravananArtur Schmidtchen

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.

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Citations

Jan 3, 2019·Chemistry : a European Journal·Xueyan FengLi Yao
Aug 13, 2020·Critical Reviews in Biotechnology·Margit MahlapuuJonas Ekblom
Jan 3, 2020·Science Translational Medicine·Manoj PuthiaArtur Schmidtchen
Aug 17, 2020·International Journal of Molecular Sciences·Surajit Bhattacharjya, Suzana K Straus
Nov 20, 2020·Expert Review of Anti-infective Therapy·Klaus BrandenburgPatrick Garidel
Jul 28, 2019·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Daniel A HoldbrookPeter J Bond
Dec 10, 2020·Journal of Molecular Cell Biology·Ganna PetrukAnd Artur Schmidtchen
Feb 7, 2021·International Journal of Molecular Sciences·Rachita Dash, Surajit Bhattacharjya
Mar 16, 2021·Frontiers in Immunology·Rathi SaravananArtur Schmidtchen
Apr 4, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Charlotte M J WesselingNathaniel I Martin
May 6, 2021·Acta Biomaterialia·Ann-Charlotte StrömdahlManoj Puthia
Jul 21, 2021·Bioconjugate Chemistry·Humaira IlyasMartin Malmsten
Aug 24, 2021·Antimicrobial Agents and Chemotherapy·Anna DahlmanGanna Petruk

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Methods Mentioned

BETA
electron microscopy
NMR
microscale thermophoresis
circular dichroism
circular
Fusion Tribrid

Software Mentioned

CYANA
CHARMM27
ClusPro
States
Modeller
MolMol
MARTINI
StavroX
VMD
Graph Pad Prism

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