Please use this identifier to cite or link to this item: https://hdl.handle.net/10356/88214
Title: Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides
Authors: Saravanan, Rathi
Holdbrook, Daniel A
Petrlova, Jitka
Singh, Shalini
Berglund, Nils A
Choong, Yeu Khai
Kjellström, Sven
Bond, Peter J
Malmsten, Martin
Schmidtchen, Artur
Keywords: Thrombin-derived C-terminal Peptides
Endotoxin
DRNTU::Science::Medicine
Issue Date: 2018
Source: Saravanan, R., Holdbrook, D. A., Petrlova, J., Singh, S., Berglund, N. A., Choong, Y. K., . . . Schmidtchen, A. (2018). Structural basis for endotoxin neutralisation and anti-inflammatory activity of thrombin-derived C-terminal peptides. Nature Communications, 9(1), 2762-. doi:10.1038/s41467-018-05242-0
Series/Report no.: Nature Communications
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.
URI: https://hdl.handle.net/10356/88214
http://hdl.handle.net/10220/45669
DOI: http://dx.doi.org/10.1038/s41467-018-05242-0
Rights: © 2018 The Author(s) (Nature Publishing Group). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:LKCMedicine Journal Articles

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