TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS

Structurally disparate molecules reportedly engage and activate Toll-like receptor (TLR) 4 and other TLRs, yet the interactions that mediate binding and activation by dissimilar ligands remain unknown. We describe Neoseptins, chemically synthesized peptidomimetics that bear no structural similarity...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 7; pp. E884 - E893
Main Authors: Wang, Ying, Su, Lijing, Morin, Matthew D, Jones, Brian T, Whitby, Landon R, Surakattula, Murali M R P, Huang, Hua, Shi, Hexin, Choi, Jin Huk, Wang, Kuan-wen, Moresco, Eva Marie Y, Berger, Michael, Zhan, Xiaoming, Zhang, Hong, Boger, Dale L, Beutler, Bruce
Format: Journal Article
Language:English
Published: United States 16.02.2016
Subjects:
Animals
Lipopolysaccharides - pharmacology
Lymphocyte Antigen 96 - agonists
Mice
Mice, Inbred C57BL
Mice, Transgenic
Mitogen-Activated Protein Kinases - metabolism
NF-kappa B - metabolism
Peptidomimetics - pharmacology
Protein-Serine-Threonine Kinases - metabolism
Signal Transduction
Toll-Like Receptor 4 - agonists
crystal structure
proinflammatory response
innate immunity
peptidomimetic compounds
neoseptins
ISSN:1091-6490
Online Access:Get more information
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Summary:Structurally disparate molecules reportedly engage and activate Toll-like receptor (TLR) 4 and other TLRs, yet the interactions that mediate binding and activation by dissimilar ligands remain unknown. We describe Neoseptins, chemically synthesized peptidomimetics that bear no structural similarity to the established TLR4 ligand, lipopolysaccharide (LPS), but productively engage the mouse TLR4 (mTLR4)/myeloid differentiation factor 2 (MD-2) complex. Neoseptin-3 activates mTLR4/MD-2 independently of CD14 and triggers canonical myeloid differentiation primary response gene 88 (MyD88)- and Toll-interleukin 1 receptor (TIR) domain-containing adaptor inducing IFN-beta (TRIF)-dependent signaling. The crystal structure mTLR4/MD-2/Neoseptin-3 at 2.57-Å resolution reveals that Neoseptin-3 binds as an asymmetrical dimer within the hydrophobic pocket of MD-2, inducing an active receptor complex similar to that induced by lipid A. However, Neoseptin-3 and lipid A form dissimilar molecular contacts to achieve receptor activation; hence strong TLR4/MD-2 agonists need not mimic LPS.
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ISSN:1091-6490
DOI:10.1073/pnas.1525639113