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首页> 外文期刊>Journal of Molecular Biology >Structural basis of the preferential binding for globo-series glycosphingolipids displayed by Pseudomonas aeruginosa lectin I.
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Structural basis of the preferential binding for globo-series glycosphingolipids displayed by Pseudomonas aeruginosa lectin I.

机译：铜绿假单胞菌凝集素I展示的球系列糖鞘脂优先结合的结构基础。

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摘要

The opportunistic pathogen Pseudomonas aeruginosa contains several carbohydrate-binding proteins, among which is the P. aeruginosa lectin I (PA-IL), which displays affinity for alpha-galactosylated glycans. Glycan arrays were screened and demonstrated stronger binding of PA-IL toward alphaGal1-4betaGal-terminating structures and weaker binding to alphaGal1-3betaGal ones in order to determine which human glycoconjugates could play a role in the carbohydrate-mediated adhesion of the bacteria. This was confirmed in vivo by testing the binding of the lectin to Burkitt lymphoma cells that present large amounts of globotriaosylceramide antigen Gb3/CD77/P(k). Trisaccharide moieties of Gb3 (alphaGal1-4betaGal1-4Glc) and isoglobotriaosylceramide (alphaGal1-3betaGal1-4Glc) were tested by titration microcalorimetry, and both displayed similar affinity to PA-IL in solution. The crystal structure of PA-IL complexed to alphaGal1-3betaGal1-4Glc trisaccharide has been solved at 1.9-A resolution and revealed how the second galactose residue makes specific contacts with the protein surface. Molecular modeling studies were performed in order to compare the binding mode of PA-IL toward alphaGal1-3Gal with that toward alphaGal1-4Gal. Docking studies demonstrated that alphaGal1-4Gal creates another network of contacts for achieving a very similar affinity, and 10-ns molecular dynamics in explicit water allowed for analyzing the flexibility of each disaccharide ligand in the protein binding site. The higher affinity observed for binding to Gb3 epitope, both in vivo and on glycan array, is likely related to the presentation effect of the oligosaccharide on a surface, since only the Gb3 glycosphingolipid geometry is fully compatible with parallel insertion of neighboring trisaccharide heads in two binding sites of the same tetramer of PA-IL.
机译：机会病原体铜绿假单胞菌含有几种碳水化合物结合蛋白，其中包括铜绿假单胞菌凝集素I（PA-IL），它对α-半乳糖基化聚糖具有亲和力。筛选了聚糖阵列，并证明了PA-IL与alphaGal1-4betaGal终止结构的结合更强，而与alphaGal1-3betaGal结合的结构较弱，从而确定了哪些人糖缀合物可以在碳水化合物介导的细菌黏附中发挥作用。在体内通过测试凝集素与存在大量globotriaosylceramide抗原Gb3 / CD77 / P（k）的Burkitt淋巴瘤细胞的结合，证实了这一点。通过滴定微量量热法测试了Gb3（alphaGal1-4betaGal1-4Glc）和异globotriaosylceramide（alphaGal1-3betaGal1-4Glc）的三糖部分，两者在溶液中均显示出与PA-IL相似的亲和力。与αGal1-3betaGal1-4Glc三糖复合的PA-IL的晶体结构已在1.9-A分辨率下解析，并揭示了第二个半乳糖残基如何与蛋白质表面形成特异性接触。为了比较PA-IL与αGal1-3Gal的结合模式与对αGal1-4Gal的结合模式，进行了分子建模研究。对接研究表明，alphaGal1-4Gal建立了另一个接触网络，以实现非常相似的亲和力，并且在显性水中的10 ns分子动力学可以分析蛋白质结合位点中每个二糖配体的柔性。在体内和在聚糖阵列上观察到的与Gb3表位结合的较高亲和力可能与寡糖在表面上的呈递作用有关，因为只有Gb3糖鞘脂的几何结构与相邻的三糖头平行插入两个完全相容PA-IL相同四聚体的结合位点。

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