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首页> 外文期刊>Journal of the American Chemical Society >Dissecting Multivalent Lectin-Carbohydrate Recognition Using Polyvalent Multifunctional Glycan-Quantum Dots
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Dissecting Multivalent Lectin-Carbohydrate Recognition Using Polyvalent Multifunctional Glycan-Quantum Dots

机译：剖析多价多功能糖-量子点的多价凝集素-碳水化合物识别。

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摘要

Multivalent protein-carbohydrate interactions initiate the first contacts between virus/bacteria and target cells, which ultimately lead to infection. Understanding the structures and binding modes involved is vital to the design of specific, potent multivalent inhibitors. However, the lack of structural information on such flexible, complex, and multimeric cell surface membrane proteins has often hampered such endeavors. Herein, we report that quantum dots (QDs) displayed with a dense array of mono-/disaccharides are powerful probes for multivalent protein-glycan interactions. Using a pair of closely related tetrameric lectins, DC-SIGN and DC-SIGNR, which bind to the HIV and Ebola virus glycoproteins (EBOV-GP) to augment viral entry and infect target cells, we show that such QDs efficiently dissect the different DC-SIGN/R-glycan binding modes (tetra-/di-/monovalent) through a combination of multimodal readouts: Förster resonance energy transfer (FRET), hydrodynamic size measurement, and transmission electron microscopy imaging. We also report a new QD-FRET method for quantifying QD-DC-SIGN/R binding affinity, revealing that DC-SIGN binds to the QD >100-fold tighter than does DC-SIGNR. This result is consistent with DC-SIGN's higher trans-infection efficiency of some HIV strains over DC-SIGNR. Finally, we show that the QDs potently inhibit DC-SIGN-mediated enhancement of EBOV-GP-driven transduction of target cells with IC_(50) values down to 0.7 nM, matching well to their DC-SIGN binding constant (apparent K_d = 0.6 nM) measured by FRET. These results suggest that the glycan-QDs are powerful multifunctional probes for dissecting multivalent protein-ligand recognition and predicting glyconanoparticle inhibition of virus infection at the cellular level.
机译：多价蛋白质与碳水化合物的相互作用会引发病毒/细菌与靶细胞之间的首次接触，最终导致感染。了解涉及的结构和结合模式对于设计有效的多价抑制剂至关重要。但是，缺乏关于这种柔性，复杂和多聚体细胞表面膜蛋白的结构信息常常阻碍了这种努力。在这里，我们报告密集的单糖/二糖阵列显示的量子点（QDs）是多价蛋白质-聚糖相互作用的有力探针。使用一对紧密相关的四聚体凝集素DC-SIGN和DC-SIGNR，它们与HIV和埃博拉病毒糖蛋白（EBOV-GP）结合以增加病毒进入并感染靶细胞，我们证明了这些QD可以有效地解剖不同的DC -SIGN / R-聚糖结合模式（四价/二价/单价）通过多模式读数的组合进行：福斯特共振能量转移（FRET），流体动力学尺寸测量和透射电子显微镜成像。我们还报告了一种新的QD-FRET方法，用于量化QD-DC-SIGN / R的结合亲和力，揭示了DC-SIGN与QD的结合比DC-SIGNR更紧密> 100倍。该结果与DC-SIGNR对某些HIV菌株的更高的转染效率相一致。最后，我们显示，量子点有效抑制EBOV-GP驱动的靶细胞的DC-SIGN介导的增强，IC_（50）值低至0.7 nM，与其DC-SIGN结合常数良好匹配（表观K_d = 0.6 nM）由FRET测量。这些结果表明，聚糖-QD是用于解剖多价蛋白-配体识别并预测糖纳米颗粒在细胞水平抑制病毒感染的强大多功能探针。

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  • 来源
    《Journal of the American Chemical Society》 |2017年第34期|11833-11844|共12页
  • 作者

    Guo Yuan; Nehlmeier Inga; Poole Emma; Sakonsinsiri Chadamas; Hondow Nicole S.; Brown Andrew P.; Li Qing; Li Shuang; Whitworth Jessie; Li Zhongjun; Yu Anchi; Rik M D Brydson Rik; W. Bruce Turnbull W.; Pöhlmann Stefan; Dejian Zhou Dejian;

  • 作者单位

    School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom;

    Infection Biology Unit, German Primate Center, Kellnerweg 4, Gottingen, Germany;

    School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom;

    School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom,Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand;

    School of Chemical and Process Engineering, University of Leeds, Leeds, United Kingdom;

    School of Chemical and Process Engineering, University of Leeds, Leeds, United Kingdom;

    Department of Chemical Biology, Peking University Health Sciences Centre, Beijing, China;

    Department of Chemistry, Renmin University of China, Beijing, China;

    School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom;

    Department of Chemical Biology, Peking University Health Sciences Centre, Beijing, China;

    Department of Chemistry, Renmin University of China, Beijing, China;

    School of Chemical and Process Engineering, University of Leeds, Leeds, United Kingdom;

    School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom;

    Infection Biology Unit, German Primate Center, Kellnerweg 4, Gottingen, Germany;

    School of Chemistry, Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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