The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex
The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex
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DOI：
10.1038/nature07830
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发表时间：
2009-04-30
期刊：
影响因子：
64.8
通讯作者：
Lee, Jie-Oh
中科院分区：
文献类型：
--
作者：
Park, Beom Seok;Song, Dong Hyun;Lee, Jie-Oh
革兰氏阴性菌的脂多糖（LPS）是一种众所周知的先天免疫应答诱导剂（1）。Toll样受体（TLR）4和髓样分化因子2（MD-2）形成异源二聚体，其识别结构多样的LPS分子中的共同“模式”。为了了解TLR 4-MD-2-LPS复合物的配体特异性和受体激活机制，我们测定了其晶体结构。LPS结合诱导形成由两个对称排列的TLR 4-MD-2-LPS复合物拷贝组成的m形受体多聚体。LPS与MD-2中的大疏水口袋相互作用，并直接桥接多聚体的两个组分。LPS的六条脂质链中的五条深埋在口袋内，剩余的链暴露于MD-2的表面，与TLR 4的保守苯丙氨酸形成疏水相互作用。MD-2的F126环经历局部结构变化，并通过与TLR 4进行亲水性相互作用来支持该核心疏水界面。与MD-2结合的四酰化拮抗剂的结构比较表明，LPS中的两个其它脂质链将磷酸化葡糖胺骨架向溶剂区域置换了约5埃（2，3）。这种结构转变允许LPS的磷酸基团通过与TLR 4和MD-2中带正电荷的残基簇形成离子相互作用而促进受体多聚化。TLR 4-MD-2-LPS结构说明TLR家族所采用的配体识别机制的显著通用性（4，5），这对于防御各种微生物感染是必不可少的。
The lipopolysaccharide (LPS) of Gram negative bacteria is a well-known inducer of the innate immune response(1). Toll-like receptor (TLR) 4 and myeloid differentiation factor 2 (MD-2) form a heterodimer that recognizes a common 'pattern' in structurally diverse LPS molecules. To understand the ligand specificity and receptor activation mechanism of the TLR4-MD-2-LPS complex we determined its crystal structure. LPS binding induced the formation of an m-shaped receptor multimer composed of two copies of the TLR4-MD-2-LPS complex arranged symmetrically. LPS interacts with a large hydrophobic pocket in MD-2 and directly bridges the two components of the multimer. Five of the six lipid chains of LPS are buried deep inside the pocket and the remaining chain is exposed to the surface of MD-2, forming a hydrophobic interaction with the conserved phenylalanines of TLR4. The F126 loop of MD-2 undergoes localized structural change and supports this core hydrophobic interface by making hydrophilic interactions with TLR4. Comparison with the structures of tetra-acylated antagonists bound to MD-2 indicates that two other lipid chains in LPS displace the phosphorylated glucosamine backbone by similar to 5 angstrom towards the solvent area(2,3). This structural shift allows phosphate groups of LPS to contribute to receptor multimerization by forming ionic interactions with a cluster of positively charged residues in TLR4 and MD-2. The TLR4-MD-2-LPS structure illustrates the remarkable versatility of the ligand recognition mechanisms employed by the TLR family(4,5), which is essential for defence against diverse microbial infection.