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

Academic Article
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Overview

related to degree

  • Whitby, Landon, Ph.D. in Chemical Biology, Scripps Research 2005 - 2011

authors

  • Wang, Y.
  • Su, L.
  • Morin, M. D.
  • Jones, B. T.
  • Whitby, Landon
  • Surakattula, M. M. R. P.
  • Huang, H.
  • Shi, H.
  • Choi, J. H.
  • Wang, K. W.
  • Moresco, E. M. Y.
  • Berger, M.
  • Zhan, X.
  • Zhang, H.
  • Boger, Dale
  • Beutler, Bruce

publication date

  • 2016

journal

  • Proceedings of the National Academy of Sciences of the United States of America  Journal

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 areas

  • Animals
  • Lipopolysaccharides
  • Lymphocyte Antigen 96
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitogen-Activated Protein Kinases
  • NF-kappa B
  • Peptidomimetics
  • Protein-Serine-Threonine Kinases
  • Signal Transduction
  • Toll-Like Receptor 4
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Identity

PubMed Central ID

  • PMC4763747

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.1525639113

PubMed ID

  • 26831104
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Additional Document Info

start page

  • E884

end page

  • E893

volume

  • 113

issue

  • 7

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