Molecular insights into the interaction between Plasmodium falciparum apical membrane antigen 1 and an invasion-inhibitory peptide

Geqing Wang, Christopher Andrew MacRaild, Biswaranjan Mohanty, Mehdi Mobli, Nathan Philip Cowieson, Robin F Anders, Jamie Scott Simpson, Sheena McGowan, Raymond Stanley Norton, Martin Scanlon

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Apical membrane antigen 1 (AMA1) of the human malaria parasite Plasmodium falciparum has been implicated in invasion of the host erythrocyte. It interacts with malarial rhoptry neck (RON) proteins in the moving junction that forms between the host cell and the invading parasite. Agents that block this interaction inhibit invasion and may serve as promising leads for anti-malarial drug development. The invasion-inhibitory peptide R1 binds to a hydrophobic cleft on AMA1, which is an attractive target site for small molecules that block parasite invasion. In this work, truncation and mutational analyses show that Phe5-Phe9, Phe12 and Arg15 in R1 are the most important residues for high affinity binding to AMA1. These residues interact with two well-defined binding hot spots on AMA1. Computational solvent mapping reveals that one of these hot spots is suitable for small molecule targeting. We also confirm that R1 in solution binds to AMA1 with 1:1 stoichiometry and adopts a secondary structure consistent with the major form of R1 observed in the crystal structure of the complex. Our results provide a basis for designing high affinity inhibitors of the AMA1-RON2 interaction.
Original languageEnglish
Pages (from-to)1-12
Number of pages12
JournalPLoS ONE
Volume9
Issue number10
DOIs
Publication statusPublished - 2014

Cite this

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title = "Molecular insights into the interaction between Plasmodium falciparum apical membrane antigen 1 and an invasion-inhibitory peptide",
abstract = "Apical membrane antigen 1 (AMA1) of the human malaria parasite Plasmodium falciparum has been implicated in invasion of the host erythrocyte. It interacts with malarial rhoptry neck (RON) proteins in the moving junction that forms between the host cell and the invading parasite. Agents that block this interaction inhibit invasion and may serve as promising leads for anti-malarial drug development. The invasion-inhibitory peptide R1 binds to a hydrophobic cleft on AMA1, which is an attractive target site for small molecules that block parasite invasion. In this work, truncation and mutational analyses show that Phe5-Phe9, Phe12 and Arg15 in R1 are the most important residues for high affinity binding to AMA1. These residues interact with two well-defined binding hot spots on AMA1. Computational solvent mapping reveals that one of these hot spots is suitable for small molecule targeting. We also confirm that R1 in solution binds to AMA1 with 1:1 stoichiometry and adopts a secondary structure consistent with the major form of R1 observed in the crystal structure of the complex. Our results provide a basis for designing high affinity inhibitors of the AMA1-RON2 interaction.",
author = "Geqing Wang and MacRaild, {Christopher Andrew} and Biswaranjan Mohanty and Mehdi Mobli and Cowieson, {Nathan Philip} and Anders, {Robin F} and Simpson, {Jamie Scott} and Sheena McGowan and Norton, {Raymond Stanley} and Martin Scanlon",
year = "2014",
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pages = "1--12",
journal = "PLoS ONE",
issn = "1932-6203",
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Molecular insights into the interaction between Plasmodium falciparum apical membrane antigen 1 and an invasion-inhibitory peptide. / Wang, Geqing; MacRaild, Christopher Andrew; Mohanty, Biswaranjan; Mobli, Mehdi; Cowieson, Nathan Philip; Anders, Robin F; Simpson, Jamie Scott; McGowan, Sheena; Norton, Raymond Stanley; Scanlon, Martin.

In: PLoS ONE, Vol. 9, No. 10, 2014, p. 1-12.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Mohanty, Biswaranjan

AU - Mobli, Mehdi

AU - Cowieson, Nathan Philip

AU - Anders, Robin F

AU - Simpson, Jamie Scott

AU - McGowan, Sheena

AU - Norton, Raymond Stanley

AU - Scanlon, Martin

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