Structure and Dynamics of Apical Membrane Antigen 1 from Plasmodium falciparum FVO

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• 作者：San Sui Lim ; Wei Yang ; Bankala Krishnarjuna ; Komagal Kannan Sivaraman ; Indu R. Chandrashekaran ; Itamar Kass ; Christopher A. MacRaild ; Shane M. Devine ; Cael O. Debono ; Robin F. Anders ; Martin J. Scanlon ; Peter J. Scammells ; Raymond S. Norton ; Sheena McGowan
• 刊名：Biochemistry
• 出版年：2014
• 出版时间：November 25, 2014
• 年：2014
• 卷：53
• 期：46
• 页码：7310-7320
• 全文大小：568K
• ISSN：1520-4995

文摘

Apical membrane antigen 1 (AMA1) interacts with RON2 to form a protein complex that plays a key role in the invasion of host cells by malaria parasites. Blocking this protein鈥損rotein interaction represents a potential route to controlling malaria and related parasitic diseases, but the polymorphic nature of AMA1 has proven to be a major challenge to vaccine-induced antibodies and peptide inhibitors exerting strain-transcending inhibitory effects. Here we present the X-ray crystal structure of AMA1 domains I and II from Plasmodium falciparum strain FVO. We compare our new structure to those of AMA1 from P. falciparum 3D7 and Plasmodium vivax. A combination of normalized B factor analysis and computational methods has been used to investigate the flexibility of the domain I loops and how this correlates with their roles in determining the strain specificity of human antibody responses and inhibitory peptides. We also investigated the domain II loop, a key region involved in inhibitor binding, by comparison of multiple AMA1 crystal structures. Collectively, these results provide valuable insights that should contribute to the design of strain-transcending agents targeting P. falciparum AMA1.