Multiple modes of binding enhance the affinity of DC-SIGN for high mannose N-linked glycans found on viral glycoproteins
Multiple modes of binding enhance the affinity of DC-SIGN for high mannose N-linked glycans found on viral glycoproteins
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DOI：
10.1074/jbc.m609689200
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发表时间：
2007-02-09
影响因子：
4.8
通讯作者：
Weis, William I.
中科院分区：
文献类型：
--
作者：
Feinberg, Hadar;Castelli, Riccardo;Weis, William I.
树突状细胞表面受体DC-SIGN和密切相关的内皮细胞受体DC-SIGNR特异性识别病毒病原体上的高甘露糖N-连接碳水化合物。先前的研究表明，这些受体结合高甘露糖结构中存在的外三甘露糖分支Man α 1-3[Manal-6]Man α。尽管三甘露糖苷与DC-SIGN或DC-SIGNR的结合比甘露糖更强，但在寡聚甘露糖结构的非还原末端上存在一个或多个Man α 1- 2 Man α部分的情况下观察到额外的亲和力增强。通过测定与高甘露糖N-连接寡糖的合成六甘露糖片段Man alpha 1- 2 Man alpha 1-3[Man alpha 1 - 2 Man alpha 1-6]Man alpha-6 Man和二糖Man alpha 1- 2 Man结合的DC-SIGN的晶体结构，研究了这种增强的分子基础。结构揭示了在每种情况下两种结合模式的混合物。每种模式的特点是典型的C型凝集素结合在主要的Ca 2+结合位点的一个甘露糖残基。此外，其他糖残基形成每种结合模式特有的接触。这些结果表明，显示朝向修饰Mana 1 - 2 Mana结构的寡糖的亲和力增强部分是由于在初级Ca 21位点的多种结合模式，其提供额外的接触和统计（熵）结合增强。
The dendritic cell surface receptor DC-SIGN and the closely related endothelial cell receptor DC-SIGNR specifically recognize high mannose N-linked carbohydrates on viral pathogens. Previous studies have shown that these receptors bind the outer trimannose branch Man alpha 1-3[Manal-6]Man alpha present in high mannose structures. Although the trimannoside binds to DC-SIGN or DC-SIGNR more strongly than mannose, additional affinity enhancements are observed in the presence of one or more Man alpha 1-2Man alpha moieties on the nonreducing termini of oligomannose structures. The molecular basis of this enhancement has been investigated by determining crystal structures of DC-SIGN bound to a synthetic six-mannose fragment of a high mannose N-linked oligosaccharide, Man alpha 1-2Man alpha 1-3[Man alpha 1-2Man alpha 1-6]Man alpha-6Man and to the disaccharide Man alpha 1-2Man. The structures reveal mixtures of two binding modes in each case. Each mode features typical C-type lectin binding at the principal Ca2+-binding site by one mannose residue. In addition, other sugar residues form contacts unique to each binding mode. These results suggest that the affinity enhancement displayed toward oligosaccharides decorated with the Mana1-2Mana structure is due in part to multiple binding modes at the primary Ca 21 site, which provide both additional contacts and a statistical (entropic) enhancement of binding.