期刊
NATURE COMMUNICATIONS
卷 9, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-05242-0
关键词
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资金
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore Start-Up Grant
- Lee Kong Chian School of Medicine
- Singapore Ministry of Education [2015-T1-001-082]
- Knut and Alice Wallenberg Foundation
- Swedish Foundation for Strategic Research
- Swedish Research Council projects [2012-1883, 2017-02341]
- LEO Foundation Center for Cutaneous Drug Delivery [2016-11-01]
- [2016-05157]
- LEO Foundation [LF15007] Funding Source: researchfish
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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