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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Structure of AMA1 from Plasmodium falciparum reveals a clustering of polymorphisms that surround a conserved hydrophobic pocket
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Structure of AMA1 from Plasmodium falciparum reveals a clustering of polymorphisms that surround a conserved hydrophobic pocket

机译：恶性疟原虫AMA1的结构揭示了围绕一个保守的疏水口袋的多态性簇。

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摘要

Apical membrane antigen 1 (AMA1) is a leading malaria vaccine candidate that possesses polymorphisms that may pose a problem for a vaccine based on this antigen. Knowledge of the distribution of the polymorphic sites on the surface of AMA1 is necessary to obtain a detailed understanding of their significance for vaccine development. For this reason we have sought to determine the three-dimensional structure of AMA1 using x-ray crystallography. The central two-thirds of AMA1 is relatively conserved among Plasmodium species as well as more distantly related apicomplexan parasites, and contains two clusters of disulfide-bonded cysteines termed domains I and II. The crystal structure of this fragment of AMA1 reported here reveals that domains I+II consists of two intimately associated PAN domains. PAN domain I contains many long loops that extend from the domain core and form a scaffold for numerous polymorphic residues. This extreme adaptation of a PAN domain reveals how malaria parasites have introduced significant flexibility and variation into AMA1 to evade protective human antibody responses. The polymorphisms on the AMA1 surface are exclusively located on one side of the molecule, presumably because this region of AMA1 is most accessible to antibodies reacting with the parasite surface. Moreover, the most highly polymorphic residues surround a conserved hydrophobic trough that is ringed by domain I and domain II loops. Precedents set by viral receptor proteins would suggest that this is likely to be the AMA1 receptor binding pocket.
机译：根尖膜抗原1（AMA1）是领先的疟疾疫苗候选者，它具有多态性，可能对该基于该抗原的疫苗造成问题。必须了解AMA1表面多态性位点的分布，才能详细了解其对疫苗开发的重要性。因此，我们试图使用X射线晶体学确定AMA1的三维结构。 AMA1的中央三分之二在疟原虫物种以及更远距离相关的apicomplexan寄生虫中相对保守，并且包含两个二硫键结合的半胱氨酸簇，分别称为结构域I和II。此处报道的AMA1片段的晶体结构表明，域I + II由两个紧密相关的PAN域组成。 PAN结构域I包含许多从结构域核心延伸的长环，并形成多个多态残基的支架。 PAN域的这种极端适应性揭示了疟原虫如何将显着的灵活性和变异性引入AMA1中，从而逃避了保护性人类抗体反应。 AMA1表面上的多态性仅位于分子的一侧，可能是因为与寄生虫表面反应的抗体最容易接近AMA1的这一区域。此外，最高度多态的残基围绕着保守的疏水槽，该疏水槽被结构域I和结构域II环环化。受病毒受体蛋白影响的先例表明这很可能是AMA1受体结合袋。

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