Journal Article

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

Morin, Matthew D., Berger, Michael, Zhan, Xiaoming, Choi, Jin Huk, Wang, Kuan-wen, Wang, Ying, Zhang, Hong, Beutler, Bruce, Boger, Dale L., Su, Lijing, Jones, Brian T., Whitby, Landon R., Moresco, Eva Marie Y., Shi, Hexin, Surakattula, Murali M. R. P., Huang, Hua

2016

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Animals / BASIC BIOLOGICAL SCIENCES / Biological Sciences / Crystal structure / Cytokines / Immunology and Inflammation / innate immunity / INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY / Ligands / Lipids / Lipopolysaccharides - pharmacology / Lymphocyte Antigen 96 - agonists / Mice / Mice, Inbred C57BL / Mice, Transgenic / Mitogen-Activated Protein Kinases - metabolism / Molecules / neoseptins / NF-kappa B - metabolism / peptidomimetic compounds / Peptidomimetics - pharmacology / PNAS Plus / proinflammatory response / Protein-Serine-Threonine Kinases - metabolism / Rodents / Signal Transduction / Toll-Like Receptor 4 - agonists