Structural basis of species-specific endotoxin sensing by innate immune receptor TLR4/MD-2

被引：279

作者：

Ohto, Umeharu ^{[1
,2
]}

Fukase, Koichi ^{[3
]}

Miyake, Kensuke ^{[4
]}

Shimizu, Toshiyuki ^{[1
,2
]}

机构：

[1] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan

[2] RIKEN SPring 8 Ctr, Sayo, Hyogo 6795148, Japan

[3] Osaka Univ, Grad Sch Sci, Dept Chem, Toyonaka, Osaka 5600043, Japan

[4] Univ Tokyo, Inst Med Sci, Div Infect Genet, Minato Ku, Tokyo 1088639, Japan

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2012年 / 109卷 / 19期

关键词：

LIPID-A; CRYSTAL-STRUCTURE; MD-2; TLR4; ANTAGONIST; BACTERIAL; RESPONSIVENESS; RECOGNITION; RESIDUES; COMPLEX;

D O I：

10.1073/pnas.1201193109

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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 angstrom 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.

引用

页码：7421 / 7426

页数：6

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