Evaluation of the carbohydrate recognition domain of the bacterial adhesin FimH: design, synthesis and binding properties of mannoside ligands
Evaluation of the carbohydrate recognition domain of the bacterial adhesin FimH: design, synthesis and binding properties of mannoside ligands
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DOI：
10.1039/b610745a
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发表时间：
2006-01-01
影响因子：
3.2
通讯作者：
Lindhorst, Thisbe K.
中科院分区：
文献类型：
--
作者：
Sperling, Oliver;Fuchs, Andreas;Lindhorst, Thisbe K.
菌毛是细菌表面的蛋白质附属物，介导细菌与宿主细胞糖萼的粘附。所谓的 1 型菌毛对 α-D-甘露糖苷表现出特异性，因此，它们被认为通过菌毛凝集素和暴露在宿主细胞表面的 α-D-甘露糖基残基的相互作用来介导细菌粘附。这种 1 型菌毛的碳水化合物特异性粘附蛋白亚基已被鉴定为一种名为 FimH 的蛋白质。这种凝集素的晶体结构是已知的，并且基于该信息，本文阐述了甘露糖苷配体和 FimH 相互作用的分子细节。基于计算机的对接方法用于评估已知配体以及设计新配体。然后，合成了一系列具有延长苷元的新甘露糖苷，并在 ELISA 中测试其作为 1 型菌毛介导的细菌粘附的抑制剂。将获得的结果与分子模型得出的预测和发现进行比较。这项研究提高了人们对正在研究的配体-受体相互作用的理解。
Fimbriae are proteinogeneous appendages on the surface of bacteria, which mediate bacterial adhesion to the host cell glycocalyx. The so-called type 1 fimbriae exhibit specificity for alpha-D-mannosides and, therefore, they are assumed to mediate bacterial adhesion via the interaction of a fimbrial lectin and alpha-D-mannosyl residues exposed on the host cell surface. This carbohydrate-specific adhesive protein subunit of type 1 fimbriae has been identified as a protein called FimH. The crystal structure of this lectin is known and, based on this information, the molecular details of the interaction of mannoside ligands and FimH are addressed in this paper. Computer-based docking methods were used to evaluate known ligands as well as to design new ones. Then, a series of new mannosides with extended aglycon was synthesized and tested as inhibitors of type 1 fimbriae-mediated bacterial adhesion in an ELISA. The results obtained were compared to the predictions and findings as delivered by molecular modeling. This study led to an improved understanding of the ligand - receptor interactions under investigation.