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

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
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  1. Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
  2. The Scripps Research Inst., La Jolla, CA (United States)
  3. The Scripps Research Inst., La Jolla, CA (United States); The Hebrew Univ. of Jerusalem (Israel)
+ Show Author Affiliations

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. Furthermore, Neoseptin-3 and lipid A form dissimilar molecular contacts to achieve receptor activation; hence strong TLR4/MD-2 agonists need not mimic LPS.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); NIH/National Institute of General Medical Sciences (NIGMS); NIH/National Institute of Allergy and Infectious Diseases (NIAID)
Grant/Contract Number:
AC02-06CH11357
OSTI ID:
1239414
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 7 Vol. 113; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

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Recent clinical trends in Toll‐like receptor targeting therapeutics journal November 2018
Immunogenicity Testing of Lipidoids In Vitro and In Silico: Modulating Lipidoid-Mediated TLR4 Activation by Nanoparticle Design journal June 2018
TLR4 signaling in VTA dopaminergic neurons regulates impulsivity through tyrosine hydroxylase modulation journal May 2016
Tannic acid prevents macrophage-induced pro-fibrotic response in lung epithelial cells via suppressing TLR4-mediated macrophage polarization journal September 2019
GABAAR α2-activated neuroimmune signal controls binge drinking and impulsivity through regulation of the CCL2/CX3CL1 balance journal April 2019
Modulators of microglial activation and polarization after intracerebral haemorrhage journal May 2017
A structural insight into the negative effects of opioids in analgesia by modulating the TLR4 signaling: An in silico approach journal December 2016
Synthetic glycan-based TLR4 agonists targeting caspase-4/11 for the development of adjuvants and immunotherapeutics journal January 2018
Phosphatidylinositol-4-kinase IIα licenses phagosomes for TLR4 signaling and MHC-II presentation in dendritic cells journal October 2020
Phosphatidylinositol-4-kinase IIα licenses phagosomes for TLR4 signaling and MHC-II presentation in dendritic cells posted_content January 2020
Exploring electrostatic patterns of human, murine, equine and canine TLR4/MD-2 receptors journal December 2019
Key residues in TLR4-MD2 tetramer formation identified by free energy simulations journal October 2019
Toll-like receptor 4 in acute viral infection: Too much of a good thing journal December 2018
TLR4 signaling improves PD-1 blockade therapy during chronic viral infection journal February 2019
Developments in anticancer vaccination: budding new adjuvants journal March 2020
Microglia in Neurological Diseases: A Road Map to Brain-Disease Dependent-Inflammatory Response journal December 2018
Computationally Designed Bispecific MD2/CD14 Binding Peptides Show TLR4 Agonist Activity journal October 2018

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
crystal structure
innate immunity
neoseptins
peptidomimetic compounds
proinflammatory response