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

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

Research output: Contribution to journalArticle

47 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)E884-E893
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number7
DOIs
StatePublished - Feb 16 2016

Fingerprint

Lipopolysaccharides
Lipid A
Ligands
Peptidomimetics
Toll-Like Receptor 4
Interleukin-1 Receptors
Genes
1-((3,5-dichloro)-2,6-dihydroxy-4-methoxyphenyl)-1-hexanone

Keywords

  • Crystal structure
  • Innate immunity
  • Neoseptins
  • Peptidomimetic compounds
  • Proinflammatory response

ASJC Scopus subject areas

  • General

Cite this

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 7, 16.02.2016, p. E884-E893.

Research output: Contribution to journalArticle

Wang, Y, Su, L, Morin, MD, Jones, BT, Whitby, LR, Surakattula, MMRP, Huang, H, Shi, H, Choi, JH, Wang, KW, Moresco, EMY, Berger, M, Zhan, X, Zhang, H, Boger, DL & Beutler, B 2016, 'TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS', Proceedings of the National Academy of Sciences of the United States of America, vol. 113, no. 7, pp. E884-E893. https://doi.org/10.1073/pnas.1525639113
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. / TLR4/MD-2 activation by a synthetic agonist with no similarity to LPS. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 7. pp. E884-E893.
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