7MLM

Crystal structure of mouse TLR4/MD-2 in complex with sulfatides

7MLM の概要

• エントリーDOI: 10.2210/pdb7mlm/pdb
• 分子名称: Toll-like receptor 4,Variable lymphocyte receptor B, Lymphocyte antigen 96, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• 機能のキーワード: innate immunity, endogenous ligands, toll-like receptors, immune system
• 由来する生物種: Mus musculus (Mouse); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 97231.32

構造登録者

Su, L.,Beutler, B. (登録日: 2021-04-28, 公開日: 2021-07-28, 最終更新日: 2024-11-06)

主引用文献

Su, L.,Athamna, M.,Wang, Y.,Wang, J.,Freudenberg, M.,Yue, T.,Wang, J.,Moresco, E.M.Y.,He, H.,Zor, T.,Beutler, B.
Sulfatides are endogenous ligands for the TLR4-MD-2 complex.
Proc.Natl.Acad.Sci.USA, 118:-, 2021

PubMed Abstract: Many endogenous molecules, mostly proteins, purportedly activate the Toll-like receptor 4 (TLR4)-myeloid differentiation factor-2 (MD-2) complex, the innate immune receptor for lipopolysaccharide (LPS) derived from gram-negative bacteria. However, there is no structural evidence supporting direct TLR4-MD-2 activation by endogenous ligands. Sulfatides (3--sulfogalactosylceramides) are natural, abundant sulfated glycolipids that have variously been shown to initiate or suppress inflammatory responses. We show here that short fatty acid (FA) chain sulfatides directly activate mouse TLR4-MD-2 independent of CD14, trigger MyD88- and TRIF-dependent signaling, and stimulate tumor necrosis factor α (TNFα) and type I interferon (IFN) production in mouse macrophages. In contrast to the agonist activity toward the mouse receptor, the tested sulfatides antagonize TLR4-MD-2 activation by LPS in human macrophage-like cells. The agonistic and antagonistic activities of sulfatides require the presence of the sulfate group and are inversely related to the FA chain length. The crystal structure of mouse TLR4-MD-2 in complex with C16-sulfatide revealed that three C16-sulfatide molecules bound to the MD-2 hydrophobic pocket and induced an active dimer conformation of the receptor complex similar to that induced by LPS or lipid A. The three C16-sulfatide molecules partially mimicked the detailed interactions of lipid A to achieve receptor activation. Our results suggest that sulfatides may mediate sterile inflammation or suppress LPS-stimulated inflammation, and that additional endogenous negatively charged lipids with up to six lipid chains of limited length might also bind to TLR4-MD-2 and activate or inhibit this complex.

PubMed: 34290146
DOI: 10.1073/pnas.2105316118

実験手法

X-RAY DIFFRACTION (2.104 Å)