2. Academic Validation
  3. TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS

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

  • Proc Natl Acad Sci U S A. 2016 Feb 16;113(7):E884-93. doi: 10.1073/pnas.1525639113.
Ying Wang 1,  Lijing Su 2,  Matthew D Morin 3,  Brian T Jones 3,  Landon R Whitby 3,  Murali M R P Surakattula 3,  Hua Huang 4,  Hexin Shi 1,  Jin Huk Choi 1,  Kuan-wen Wang 1,  Eva Marie Y Moresco 1,  Michael Berger 4,  Xiaoming Zhan 1,  Hong Zhang 5,  Dale L Boger 6,  Bruce Beutler 7
Affiliations

Affiliations

  • 1 Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390;
  • 2 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390;
  • 3 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037;
  • 4 Department of Genetics, The Scripps Research Institute, La Jolla, CA 92037.
  • 5 Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390; [email protected] [email protected] [email protected].
  • 6 Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; [email protected] [email protected] [email protected].
  • 7 Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390; [email protected] [email protected] [email protected].
PMID: 26831104 DOI: 10.1073/pnas.1525639113
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.

Keywords

crystal structure; innate immunity; neoseptins; peptidomimetic compounds; proinflammatory response.

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