High-Resolution Crystal Structures Elucidate the Molecular Basis of Cholera Blood Group Dependence.
High-Resolution Crystal Structures Elucidate the Molecular Basis of Cholera Blood Group Dependence.
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DOI：
10.1371/journal.ppat.1005567
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发表时间：
2016-04
期刊：
影响因子：
6.7
通讯作者：
Krengel U
中科院分区：
文献类型：
--
作者：
Heggelund JE;Burschowsky D;Bjørnestad VA;Hodnik V;Anderluh G;Krengel U
霍乱是血型依赖性疾病的典型例子，O 型血的人症状最严重。霍乱毒素是造成这种关系的主要嫌疑人。我们报告了经典和 El Tor 生物型的天然霍乱毒素 B 五聚体的高分辨率晶体结构 (1.1–1.6 Å)，与相关血型决定簇及其主要受体 GM1 神经节苷脂的片段形成复合物。与之前发表的霍乱毒素结构相比，A 型血决定簇以相反的方向结合，而 H 型血决定簇（O 型血的特征）以两个方向结合。如表面等离子共振所示，H 决定簇的结合亲和力高于 A 决定簇。总之，这些发现表明为什么 O 型血是严重霍乱的危险因素。霍乱是一种严重的腹泻病，每年导致十万人死亡。随着气候变化，病例数量预计将增加到数百万。 O 型血的个体尤其面临风险。在这里，我们报告了两种主要生物型的天然霍乱毒素的高分辨率晶体结构，以及与相关血型决定因素的复合物。这些结构与定量结合数据相结合，揭示了霍乱血型依赖性。了解这种关联的分子基础预计将非常重要，例如对于开发考虑到这一信息的新疫苗接种策略。
Cholera is the prime example of blood-group-dependent diseases, with individuals of blood group O experiencing the most severe symptoms. The cholera toxin is the main suspect to cause this relationship. We report the high-resolution crystal structures (1.1–1.6 Å) of the native cholera toxin B-pentamer for both classical and El Tor biotypes, in complexes with relevant blood group determinants and a fragment of its primary receptor, the GM1 ganglioside. The blood group A determinant binds in the opposite orientation compared to previously published structures of the cholera toxin, whereas the blood group H determinant, characteristic of blood group O, binds in both orientations. H-determinants bind with higher affinity than A-determinants, as shown by surface plasmon resonance. Together, these findings suggest why blood group O is a risk factor for severe cholera. Cholera is a severe diarrheal disease that kills a hundred thousand people per year. With climate change, the number of cases is predicted to increase to millions. Individuals with blood group O are particularly at risk. Here we report high-resolution crystal structures of the native cholera toxin of both major biotypes, in complexes with relevant blood group determinants. These structures, in combination with quantitative binding data, shed light on cholera blood group dependence. Understanding the molecular basis of this association is expected to be of considerable importance, for example for developing new vaccination strategies that take this information into account.