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

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–protein interaction represents a potential route to controlling malaria and related parasitic diseases, but the polymorphic n...

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Bibliographic Details
Published in:Biochemistry (Easton) 2014-11, Vol.53 (46), p.7310-7320
Main Authors: Lim, San Sui, Yang, Wei, Krishnarjuna, Bankala, Kannan Sivaraman, Komagal, Chandrashekaran, Indu R, Kass, Itamar, MacRaild, Christopher A, Devine, Shane M, Debono, Cael O, Anders, Robin F, Scanlon, Martin J, Scammells, Peter J, Norton, Raymond S, McGowan, Sheena
Format: Article
Language:English
Subjects:
Antigens, Protozoan - chemistry
Crystallography, X-Ray
Humans
Malaria, Falciparum - parasitology
Membrane Proteins - chemistry
Molecular Dynamics Simulation
Plasmodium falciparum
Plasmodium falciparum - chemistry
Plasmodium vivax
Plasmodium vivax - chemistry
Protein Structure, Tertiary
Protozoan Proteins - chemistry
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Summary: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–protein 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.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi5012089