Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran.
TLR4 and MD-2 form a heterodimer that recognizes LPS (lipopolysaccharide) from Gram-negative bacteria. Eritoran is an analog of LPS that antagonizes its activity by binding to the TLR4-MD-2 complex. We determined the structure of the full-length ectodomain of the mouse TLR4 and MD-2 complex. 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. TLR4 is an atypical member of the LRR family and is composed of N-terminal, central, and C-terminal domains. The beta sheet of the central domain shows unusually small radii and large twist angles. MD-2 binds to the concave surface of the N-terminal and central domains. The interaction with Eritoran is mediated by a hydrophobic internal pocket in MD-2. Based on structural analysis and mutagenesis experiments on MD-2 and TLR4, we propose a model of TLR4-MD-2 dimerization induced by LPS.
Kim
Ho Min
HM
Department of Chemistry, Korea Advanced Institute of Science and Technology, Daejon, Korea 305-701.
Park
Beom Seok
BS
Kim
Jung-In
JI
Kim
Sung Eun
SE
Lee
Judong
J
Oh
Se Cheol
SC
Enkhbayar
Purevjav
P
Matsushima
Norio
N
Lee
Hayyoung
H
Yoo
Ook Joon
OJ
Lee
Jie-Oh
JO
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D019281:Dimerization; D004187:Disaccharides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D029941:Fish Proteins / Q000737:chemistry; D006196:Hagfishes; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007135:Immunoglobulin Variable Region / Q000737:chemistry; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D051218:Lymphocyte Antigen 96 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D040681:Structural Homology, Protein; D013403:Sugar Phosphates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism