Energetics of Endotoxin Recognition in the Toll-Like Receptor 4 Innate Immune Response.

Abstract:

:Bacterial outer membrane lipopolysaccharide (LPS) potently stimulates the mammalian innate immune system, and can lead to sepsis, the primary cause of death from infections. LPS is sensed by Toll-like receptor 4 (TLR4) in complex with its lipid-binding coreceptor MD-2, but subtle structural variations in LPS can profoundly modulate the response. To better understand the mechanism of LPS-induced stimulation and bacterial evasion, we have calculated the binding affinity to MD-2 of agonistic and antagonistic LPS variants including lipid A, lipid IVa, and synthetic antagonist Eritoran, and provide evidence that the coreceptor is a molecular switch that undergoes ligand-induced conformational changes to appropriately activate or inhibit the receptor complex. The plasticity of the coreceptor binding cavity is shown to be essential for distinguishing between ligands, whilst similar calculations for a model bacterial LPS bilayer reveal the "membrane-like" nature of the protein cavity. The ability to predict the activity of LPS variants should facilitate the rational design of TLR4 therapeutics.

journal_name

Sci Rep

journal_title

Scientific reports

authors

Paramo T,Tomasio SM,Irvine KL,Bryant CE,Bond PJ

doi

10.1038/srep17997

subject

Has Abstract

pub_date

2015-12-09 00:00:00

pages

17997

issn

2045-2322

pii

srep17997

journal_volume

5

pub_type

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