据介绍,许多病原体利用宿主细胞表面的聚糖。
然而,与高度修饰的病原体蛋白结合的聚糖配体的精确分析,可能会因重叠糖信号和/或具有已知实验限制的化合物而混淆。 “通用饱和转移分析”(uSTA)建立在现有的核磁共振光谱的基础上,为定量蛋白质-配体相互作用提供了一个自动化的工作流程。uSTA揭示了大流行的早期B源谱系 SARS-CoV-2 刺突三聚体以“末端”方式结合唾液苷糖。uSTA引导的建模和高分辨率低温电子显微镜结构暗示了尖峰N末端结构域 (NTD),并确认了末端结合。
这一发现合理化了NTD突变的影响,这些突变消除了关注的SARS CoV 2变体中的糖结合。结合早期大流行患者队列的遗传变异分析,这种结合暗示,在人肺更深处的四联N连接糖蛋白上发现的唾液酸化聚乳糖胺基序,可能与毒力和/或人畜共患病有关。
附:英文原文
Title: Pathogen-sugar interactions revealed by universal saturation transfer analysis
Author: Charles J. Buchanan, Ben Gaunt, Peter J. Harrison, Yun Yang, Jiwei Liu, Aziz Khan, Andrew M. Giltrap, Audrey Le Bas, Philip N. Ward, Kapil Gupta, Maud Dumoux, Tiong Kit Tan, Lisa Schimaski, Sergio Daga, Nicola Picchiotti, Margherita Baldassarri, Elisa Benetti, Chiara Fallerini, Francesca Fava, Annarita Giliberti, Panagiotis I. Koukos, Matthew J. Davy, Abirami Lakshminarayanan, Xiaochao Xue, Georgios Papadakis, Lachlan P. Deimel, Virgínia Casablancas-Antràs, Timothy D. W. Claridge, Alexandre M. J. J. Bonvin, Quentin J. Sattentau, Simone Furini, Marco Gori, Jiandong Huo, Raymond J. Owens, Christiane Schaffitzel, Imre Berger, Alessandra Renieri, GEN-COVID Multicenter Study, James H. Naismith, Andrew J. Baldwin, Benjamin G. Davis
Issue&Volume: 2022-06-23
Abstract: Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily-modified pathogen proteins can be confounded by overlapping sugar signals and/or compound with known experimental constraints. ‘Universal saturation transfer analysis’ (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin lineage SARS-CoV-2 spike trimer binds sialoside sugars in an ‘end-on’ manner. uSTA-guided modelling and a high-resolution cryo-electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar-binding in SARS CoV 2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins in deeper human lung as potentially relevant to virulence and/or zoonosis.
DOI: abm3125
Source: https://www.science.org/doi/10.1126/science.abm3125