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...

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Autores principales:	Geqing Wang, Christopher A MacRaild, Biswaranjan Mohanty, Mehdi Mobli, Nathan P Cowieson, Robin F Anders, Jamie S Simpson, Sheena McGowan, Raymond S Norton, Martin J Scanlon
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a51fd55313c34feba2785836de28f0c3
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spelling	oai:doaj.org-article:a51fd55313c34feba2785836de28f0c32021-11-25T05:55:21ZMolecular insights into the interaction between Plasmodium falciparum apical membrane antigen 1 and an invasion-inhibitory peptide.1932-620310.1371/journal.pone.0109674https://doaj.org/article/a51fd55313c34feba2785836de28f0c32014-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0109674https://doaj.org/toc/1932-6203Apical 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.Geqing WangChristopher A MacRaildBiswaranjan MohantyMehdi MobliNathan P CowiesonRobin F AndersJamie S SimpsonSheena McGowanRaymond S NortonMartin J ScanlonPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 10, p e109674 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Geqing Wang Christopher A MacRaild Biswaranjan Mohanty Mehdi Mobli Nathan P Cowieson Robin F Anders Jamie S Simpson Sheena McGowan Raymond S Norton Martin J Scanlon Molecular insights into the interaction between Plasmodium falciparum apical membrane antigen 1 and an invasion-inhibitory peptide.
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	article
author	Geqing Wang Christopher A MacRaild Biswaranjan Mohanty Mehdi Mobli Nathan P Cowieson Robin F Anders Jamie S Simpson Sheena McGowan Raymond S Norton Martin J Scanlon
author_facet	Geqing Wang Christopher A MacRaild Biswaranjan Mohanty Mehdi Mobli Nathan P Cowieson Robin F Anders Jamie S Simpson Sheena McGowan Raymond S Norton Martin J Scanlon
author_sort	Geqing Wang
title	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_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_sort	molecular insights into the interaction between plasmodium falciparum apical membrane antigen 1 and an invasion-inhibitory peptide.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/a51fd55313c34feba2785836de28f0c3
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Molecular insights into the interaction between Plasmodium falciparum apical membrane antigen 1 and an invasion-inhibitory peptide.

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