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Molecular Insights into the Interaction between Plasmodium falciparum Apical Membrane Antigen 1 and an Invasion-Inhibitory Peptide
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 th...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208761/ https://www.ncbi.nlm.nih.gov/pubmed/25343578 http://dx.doi.org/10.1371/journal.pone.0109674 |
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author | Wang, Geqing MacRaild, Christopher A. Mohanty, Biswaranjan Mobli, Mehdi Cowieson, Nathan P. Anders, Robin F. Simpson, Jamie S. McGowan, Sheena Norton, Raymond S. Scanlon, Martin J. |
author_facet | Wang, Geqing MacRaild, Christopher A. Mohanty, Biswaranjan Mobli, Mehdi Cowieson, Nathan P. Anders, Robin F. Simpson, Jamie S. McGowan, Sheena Norton, Raymond S. Scanlon, Martin J. |
author_sort | Wang, Geqing |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-4208761 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-42087612014-10-27 Molecular Insights into the Interaction between Plasmodium falciparum Apical Membrane Antigen 1 and an Invasion-Inhibitory Peptide Wang, Geqing MacRaild, Christopher A. Mohanty, Biswaranjan Mobli, Mehdi Cowieson, Nathan P. Anders, Robin F. Simpson, Jamie S. McGowan, Sheena Norton, Raymond S. Scanlon, Martin J. PLoS One Research Article 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. Public Library of Science 2014-10-24 /pmc/articles/PMC4208761/ /pubmed/25343578 http://dx.doi.org/10.1371/journal.pone.0109674 Text en © 2014 Wang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Wang, Geqing MacRaild, Christopher A. Mohanty, Biswaranjan Mobli, Mehdi Cowieson, Nathan P. Anders, Robin F. Simpson, Jamie S. McGowan, Sheena Norton, Raymond S. Scanlon, Martin J. Molecular Insights into the Interaction between Plasmodium falciparum Apical Membrane Antigen 1 and an Invasion-Inhibitory Peptide |
title | Molecular Insights into the Interaction between Plasmodium falciparum Apical Membrane Antigen 1 and an Invasion-Inhibitory Peptide |
title_full | Molecular Insights into the Interaction between Plasmodium falciparum Apical Membrane Antigen 1 and an Invasion-Inhibitory Peptide |
title_fullStr | Molecular Insights into the Interaction between Plasmodium falciparum Apical Membrane Antigen 1 and an Invasion-Inhibitory Peptide |
title_full_unstemmed | Molecular Insights into the Interaction between Plasmodium falciparum Apical Membrane Antigen 1 and an Invasion-Inhibitory Peptide |
title_short | Molecular Insights into the Interaction between Plasmodium falciparum Apical Membrane Antigen 1 and an Invasion-Inhibitory Peptide |
title_sort | molecular insights into the interaction between plasmodium falciparum apical membrane antigen 1 and an invasion-inhibitory peptide |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4208761/ https://www.ncbi.nlm.nih.gov/pubmed/25343578 http://dx.doi.org/10.1371/journal.pone.0109674 |
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