| Author |
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 |
| Description |
Author Affiliation: Wang Y ( Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390); Su L ( Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390); Morin MD ( Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037); Jones BT ( Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037); Whitby LR ( Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037); Surakattula MM ( Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037); Huang H ( Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037.); Shi H ( Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390); Choi JH ( Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390); Wang KW ( Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390); Moresco EM ( Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390); Berger M ( Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037.); Zhan X ( Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390); Zhang H ( Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390); Boger DL ( Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037); Beutler B ( Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390); |
| Abstract |
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. |
| Subject Keyword |
Lipopolysaccharides Pharmacology Lymphocyte Antigen 96 Agonists Peptidomimetics Toll-Like Receptor 4 Animals Mice Mice, Inbred C57BL Mice, Transgenic Mitogen-Activated Protein Kinases Metabolism NF-kappa B Protein-Serine-Threonine Kinases Signal Transduction Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S. Multidisciplinary |
