3VQ2

Crystal structure of mouse TLR4/MD-2/LPS complex

Summary for 3VQ2

• Entry DOI: 10.2210/pdb3vq2/pdb
• Related: 3VQ1
• Descriptor: Toll-like receptor 4, Lymphocyte antigen 96, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: leucine rich repeat md-2 related lipid recognition, receptor innate immunity, lipid binding, glycosylation, secreted, immune system
• Biological source: Mus musculus (mouse); More
• Total number of polymer chains: 4
• Total formula weight: 175899.72

Authors

Ohto, U.,Shimizu, T. (deposition date: 2012-03-17, release date: 2012-05-09, Last modification date: 2024-10-30)

Primary citation

Ohto, U.,Fukase, K.,Miyake, K.,Shimizu, T.
Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2
Proc.Natl.Acad.Sci.USA, 109:7421-7426, 2012

PubMed Abstract: Lipopolysaccharide (LPS), also known as endotoxin, activates the innate immune response through toll-like receptor 4 (TLR4) and its coreceptor, MD-2. MD-2 has a unique hydrophobic cavity that directly binds to lipid A, the active center of LPS. Tetraacylated lipid IVa, a synthetic lipid A precursor, acts as a weak agonist to mouse TLR4/MD-2, but as an antagonist to human TLR4/MD-2. However, it remains unclear as to how LPS and lipid IVa show agonistic or antagonistic activities in a species-specific manner. The present study reports the crystal structures of mouse TLR4/MD-2/LPS and TLR4/MD-2/lipid IVa complexes at 2.5 and 2.7 Å resolutions, respectively. Mouse TLR4/MD-2/LPS exhibited an agonistic "m"-shaped 2:2:2 complex similar to the human TLR4/MD-2/LPS complex. Mouse TLR4/MD-2/lipid IVa complex also showed an agonistic structural feature, exhibiting architecture similar to the 2:2:2 complex. Remarkably, lipid IVa in the mouse TLR4/MD-2 complex occupied nearly the same space as LPS, although lipid IVa lacked the two acyl chains. Human MD-2 binds lipid IVa in an antagonistic manner completely differently from the way mouse MD-2 does. Together, the results provide structural evidence of the agonistic property of lipid IVa on mouse TLR4/MD-2 and deepen understanding of the ligand binding and dimerization mechanism by the structurally diverse LPS variants.

PubMed: 22532668
DOI: 10.1073/pnas.1201193109

Experimental method

X-RAY DIFFRACTION (2.48 Å)