8WTA

Cryo-EM Structure of Human TLR4/MD-2/DLAM3 Complex

8WTA の概要

• エントリーDOI: 10.2210/pdb8wta/pdb
• 関連するPDBエントリー: 8WO1 8WQT 8WRY 8WSA 9J03
• EMDBエントリー: 37831
• 分子名称: Toll-like receptor 4, Lymphocyte antigen 96, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: innate immune system, toll-like receptors, tlr4 agonist, vaccine adjuvants, disaccharide-based lipid a mimetices, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 178481.47

構造登録者

Fu, Y.,Kim, H.,Zamyatina, A.,Kim, H.M. (登録日: 2023-10-18, 公開日: 2024-10-23, 最終更新日: 2025-05-14)

主引用文献

Fu, Y.,Kim, H.,Lee, D.S.,Han, A.R.,Heine, H.,Zamyatina, A.,Kim, H.M.
Structural insight into TLR4/MD-2 activation by synthetic LPS mimetics with distinct binding modes.
Nat Commun, 16:4164-4164, 2025

PubMed Abstract: 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.

PubMed: 40325026
DOI: 10.1038/s41467-025-59550-3

実験手法

ELECTRON MICROSCOPY (2.9 Å)