Saravanan, R., Holdbrook, D.A., Petrlova, J. et al. Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides. Nat Commun 9, 2762 (2018). https://doi.org/10.1038/s41467-018-05242-0
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.
This research was supported by the Lee Kong Chian School of Medicine, Nanyang Technological University Singapore Start-Up Grant (A.S.), the Lee Kong Chian School of Medicine Postdoctoral Fellowship 2014 (RS), Singapore Ministry of Education under its Singapore Ministry of Education Academic Research Fund Tier 1 (2015-T1-001-082), the Knut and Alice Wallenberg Foundation, the Swedish Foundation for Strategic Research, the Swedish Research Council projects (projects 2012-1883 and 2017-02341) (A.S.), project 2016-05157 (M.M.), and the LEO Foundation Center for Cutaneous Drug Delivery (2016-11-01) (M.M.).