PMID: 17803912

 

    Legend: Sugar

Title : Crystal structure of the TLR4- MD-2 complex with bound endotoxin antagonist Eritoran

Abstract :

1. TLR4 and MD-2 form a heterodimer that recognizes LPS (lipopolysaccharide) from Gram-negative bacteria
2. Eritoran is an analog of LPS that antagonizes its activity by binding to the TLR4- MD-2 complex
3. We determined the structure of the full-length ectodomain of the mouse TLR4 and MD-2 complex
4. We also produced a series of hybrids of human TLR4 and hagfish VLR and determined their structures with and without bound MD-2 and Eritoran
5. TLR4 is an atypical member of the LRR family and is composed of N-terminal, central, and C-terminal domains
6. The beta sheet of the central domain shows unusually small radii and large twist angles
7. MD-2 binds to the concave surface of the N-terminal and central domains
8. The interaction with Eritoran is mediated by a hydrophobic internal pocket in MD-2
9. Based on structural analysis and mutagenesis experiments on MD-2 and TLR4 , we propose a model of TLR4- MD-2 dimerization induced by LPS