How bacterial pathogens "sweeten" host proteins to avoid immunological responses: structural study of sugar transfer by bacterial virulence factors

细菌病原体如何“甜化”宿主蛋白以避免免疫反应：细菌毒力因子糖转移的结构研究

• 批准号: 2060717
• 金额: --
• 依托单位: University of East Anglia
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2060717
• 关键词: How; bacterial; pathogens; sweeten; host

Antimicrobial resistance is one of the biggest threats to global health. To reduce it, we must ensure that antibiotics are used only where appropriate. Accordingly, other non-antibiotic approaches are welcome, and a better understanding of the biology of bacterial infections is required. Pathogens such as Salmonella and E. coli inject virulence factors (effectors) to suppress antimicrobial host responses, to promote colonisation. The NleB effector is highly conserved among pathogens. It transfers GlcNAc sugar residues to host proteins (GAPDH, FADD, TRADD), a "sweet tag" that inhibits NF-kB activation and apoptosis of infected cells, blocking major antimicrobial host responses. In this project, we will use advanced NMR spectroscopy, molecular modelling (protein-ligand docking, long molecular dynamics simulations), and other biophysical techniques (ITC) to unveil the structural features at atomic detail of the molecular recognition of host proteins by the bacterial effectors NleB1, SseK1, and SseK2. Members of this conserved family modify different host proteins and exhibit distinct modes of action to suppress host responses, but, interestingly, they differ only in a very small number of amino acids. We will try to rationalise the molecular basis of their exquisite selectivity, and the impact of sugar transfer on the interactions with other host proteins such as TRAF2.

抗生素耐药性是全球健康面临的最大威胁之一。为了减少这种情况，我们必须确保只在适当的情况下使用抗生素。因此，其他非抗生素方法是受欢迎的，需要更好地了解细菌感染的生物学。病原体如沙门氏菌和E.大肠杆菌注射毒力因子（效应子）以抑制抗微生物宿主反应，促进定殖。NleB效应子在病原体中高度保守。它将GlcNAc糖残基转移到宿主蛋白（GAPDH、FADD、TRADD），这是一种抑制NF-κ B活化和感染细胞凋亡的“甜标签”，阻断主要的抗微生物宿主反应。在这个项目中，我们将使用先进的NMR光谱，分子建模（蛋白质-配体对接，长分子动力学模拟）和其他生物物理技术（ITC）来揭示细菌效应子NleB 1，SseK 1和SseK 2对宿主蛋白质分子识别的原子细节结构特征。这个保守家族的成员修饰不同的宿主蛋白质，并表现出不同的作用模式来抑制宿主反应，但有趣的是，它们仅在极少数氨基酸上存在差异。我们将尝试合理化的分子基础，其精致的选择性，和糖转移的影响与其他宿主蛋白质，如TRAF 2的相互作用。

项目成果

Self-Correcting Method for the Measurement of Free Calcium and Magnesium Concentrations by 1H NMR.

通过 1H NMR 测量游离钙和镁浓度的自校正方法。

• DOI: 10.1021/acs.analchem.9b03008
• 发表时间: 2019
• 期刊: Analytical chemistry
• 影响因子: 7.4
• 作者: Wallace M

NleB/SseK-catalyzed arginine-glycosylation and enteropathogen virulence are finely tuned by a single variable position contiguous to the catalytic machinery.

• DOI: 10.1039/d1sc04065k
• 发表时间: 2021-09-22
• 期刊: Chemical science
• 影响因子: 8.4
• 作者: García-García A;Hicks T;El Qaidi S;Zhu C;Hardwidge PR;Angulo J;Hurtado-Guerrero R
• 通讯作者: Hurtado-Guerrero R

Fucosidases from the human gut symbiont Ruminococcus gnavus.

• DOI: 10.1007/s00018-020-03514-x
• 发表时间: 2021-01
• 期刊: Cellular and molecular life sciences : CMLS
• 作者: Wu H;Rebello O;Crost EH;Owen CD;Walpole S;Bennati-Granier C;Ndeh D;Monaco S;Hicks T;Colvile A;Urbanowicz PA;Walsh MA;Angulo J;Spencer DIR;Juge N
• 通讯作者: Juge N

Self-acetylation at the active site of phosphoenolpyruvate carboxykinase (PCK1) controls enzyme activity.

• DOI: 10.1074/jbc.ra120.015103
• 发表时间: 2021-01
• 期刊: The Journal of biological chemistry
• 作者: Latorre-Muro P;Baeza J;Hurtado-Guerrero R;Hicks T;Delso I;Hernández-Ruiz C;Velázquez-Campoy A;Lawton AJ;Angulo J;Denu JM;Carrodeguas JA
• 通讯作者: Carrodeguas JA

Fucosyltransferase-specific inhibition via next generation of fucose mimetics.

通过下一代岩藻糖模拟物进行岩藻糖基转移酶特异性抑制。

• DOI: 10.1039/d0cc04847j
• 发表时间: 2021
• 期刊: Chemical communications (Cambridge, England)
• 作者: Martin KC