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Structure paper

TitleStructural insight into TLR4/MD-2 activation by synthetic LPS mimetics with distinct binding modes.
Journal, issue, pagesNat Commun, Vol. 16, Issue 1, Page 4164, Year 2025
Publish dateMay 5, 2025
AuthorsYaoyao Fu / Hyojin Kim / Dong Sun Lee / Ah-Reum Han / Holger Heine / Alla Zamyatina / Ho Min Kim /
PubMed AbstractThe mammalian pattern-recognition receptor TLR4/MD-2 (Toll-like receptor 4/myeloid differentiation factor-2) can be activated by a wide variety of pathogen-associated and endogenous molecules, with ...The mammalian pattern-recognition receptor TLR4/MD-2 (Toll-like receptor 4/myeloid differentiation factor-2) can be activated by a wide variety of pathogen-associated and endogenous molecules, with Gram-negative bacterial lipopolysaccharide (LPS) being the primary natural TLR4 agonist. Activation of TLR4 triggers cellular signaling that enables the beneficial innate immune responses and enhances adaptive immunity, thereby emphasizing the potential of TLR4 agonists for the management of diseases with an immunopathological background and for use as vaccine adjuvants. Given the challenges associated with LPS-derived products, including structural complexity, heterogeneity, toxicity, and species specificity, synthetic molecules targeting TLR4/MD-2 offer a promising alternative. Here, we elucidate the structural basis for the recognition of synthetic LPS-mimicking glycolipids, Disaccharide Lipid A Mimetics (DLAMs), by human and mouse TLR4/MD-2 through cryo-EM structures of six dimeric [TLR4/MD-2/ligand] complexes resolved at 2.2-3.1 Å. We reveal that the specific binding modes of DLAMs, distinct from those of LPS, are essential for the species-independent TLR4 agonistic activity. DLAMs function as a molecular bridge, effectively induce the dimerization of TLR4/MD-2 complexes through specific carbohydrate structure-relevant ligand-protein interactions. Our findings reveal the distinct molecular modes of TLR4 activation, and provide a structural basis for the rationale design and development of innovative, highly potent TLR4-targeting immunotherapeutics and adjuvants.
External linksNat Commun / PubMed:40325026 / PubMed Central
MethodsEM (single particle)
Resolution2.24 - 3.1 Å
Structure data

37677

8wo1

EMDB-37677, PDB-8wo1:
Cryo-EM Structure of Human TLR4/MD-2/DLAM5 Complex
Method: EM (single particle) / Resolution: 2.24 Å

37753

8wqt

EMDB-37753, PDB-8wqt:
Cryo-EM Structure of Mouse TLR4/MD-2/DLAM1 complex
Method: EM (single particle) / Resolution: 2.6 Å

37794

8wry

EMDB-37794, PDB-8wry:
Cryo-EM Structure of Mouse TLR4/MD-2/DLAM3 Complex
Method: EM (single particle) / Resolution: 2.6 Å

37803

8wsa

EMDB-37803, PDB-8wsa:
Cryo-EM Structure of Mouse TLR4/MD-2/DLAM5 Complex
Method: EM (single particle) / Resolution: 3.1 Å

37831

8wta

EMDB-37831, PDB-8wta:
Cryo-EM Structure of Human TLR4/MD-2/DLAM3 Complex
Method: EM (single particle) / Resolution: 2.9 Å

61047

9j03

EMDB-61047, PDB-9j03:
Cyro-EM Structure of Human TLR4/MD-2/DLAM1 Complex
Method: EM (single particle) / Resolution: 2.7 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-GP4:
2-amino-2-deoxy-4-O-phosphono-alpha-D-glucopyranose

ChemComp-2IL:
(3R)-3-(dodecanoyloxy)tetradecanoic acid


ChemComp, No image

ChemComp-0IL:
Unknown entry


ChemComp, No image

ChemComp-X6N:
Unknown entry

PDB-1l01:
STRUCTURAL STUDIES OF MUTANTS OF THE LYSOZYME OF BACTERIOPHAGE T4. THE TEMPERATURE-SENSITIVE MUTANT PROTEIN THR157 (RIGHT ARROW) ILE


ChemComp, No image

ChemComp-X6Z:
Unknown entry


ChemComp, No image

ChemComp-XIQ:
Unknown entry

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsIMMUNE SYSTEM / Innate immune system / Toll-like receptors / TLR4 agonist / Vaccine adjuvants / Disaccharide-based Lipid A Mimetics / Disaccharide-based lipid A mimetices

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