TLR4-MD-2复合物识别脂多糖的结构基础,Nature

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TLR4-MD-2复合物识别脂多糖的结构基础
Nature ( IF 50.5 ) Pub Date : 2009-03-01 , DOI: 10.1038/nature07830
Beom Seok Park ₁ , Dong Hyun Song , Ho Min Kim , Byong-Seok Choi , Hayyoung Lee , Jie-Oh Lee

Affiliation

革兰氏阴性菌的脂多糖 (LPS) 是众所周知的先天免疫反应诱导剂。Toll 样受体 (TLR) 4 和髓样分化因子 2 (MD-2) 形成异二聚体，可识别结构多样的 LPS 分子中的常见“模式”。为了了解 TLR4-MD-2-LPS 复合物的配体特异性和受体激活机制，我们确定了其晶体结构。LPS 结合诱导了 m 形受体多聚体的形成，该多聚体由对称排列的 TLR4-MD-2-LPS 复合物的两个拷贝组成。LPS 与 MD-2 中的大疏水袋相互作用并直接桥接多聚体的两个组分。LPS 的 6 条脂质链中有 5 条深埋在口袋内，其余的链暴露在 MD-2 的表面，与 TLR4 的保守苯丙氨酸形成疏水相互作用。MD-2 的 F126 环发生局部结构变化，并通过与 TLR4 进行亲水相互作用来支持该核心疏水界面。与与 MD-2 结合的四酰化拮抗剂的结构进行比较表明，LPS 中的另外两条脂质链将磷酸化葡糖胺骨架向溶剂区域置换了约 5 埃。这种结构转变允许 LPS 的磷酸基团通过与 TLR4 和 MD-2 中带正电荷的残基簇形成离子相互作用来促进受体多聚化。TLR4-MD-2-LPS 结构说明了 TLR 家族采用的配体识别机制的显着多功能性，这对于防御各种微生物感染至关重要。MD-2 的 F126 环发生局部结构变化，并通过与 TLR4 进行亲水相互作用来支持该核心疏水界面。与与 MD-2 结合的四酰化拮抗剂的结构进行比较表明，LPS 中的另外两条脂质链将磷酸化葡糖胺骨架向溶剂区域置换了约 5 埃。这种结构转变允许 LPS 的磷酸基团通过与 TLR4 和 MD-2 中带正电荷的残基簇形成离子相互作用来促进受体多聚化。TLR4-MD-2-LPS 结构说明了 TLR 家族采用的配体识别机制的显着多功能性，这对于防御各种微生物感染至关重要。MD-2 的 F126 环发生局部结构变化，并通过与 TLR4 进行亲水相互作用来支持该核心疏水界面。与与 MD-2 结合的四酰化拮抗剂的结构进行比较表明，LPS 中的另外两条脂质链将磷酸化葡糖胺骨架向溶剂区域置换了约 5 埃。这种结构转变允许 LPS 的磷酸基团通过与 TLR4 和 MD-2 中带正电荷的残基簇形成离子相互作用来促进受体多聚化。TLR4-MD-2-LPS 结构说明了 TLR 家族采用的配体识别机制的显着多功能性，这对于防御各种微生物感染至关重要。

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The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex

The lipopolysaccharide (LPS) of Gram negative bacteria is a well-known inducer of the innate immune response. 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 ∼5 Å towards the solvent area. 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, which is essential for defence against diverse microbial infection.

更新日期：2009-03-01

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