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.
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Geqing
authors.initials: G
authors.lastname: Wang
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: MacRaild
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; Australian Research Council Centre of Excellence for Coherent X-ray Science, Monash University, Parkville, Victoria, Australia.
authors.forename: Biswaranjan
authors.initials: B
authors.lastname: Mohanty
authors.affiliation: Centre for Advanced Imaging, University of Queensland, St Lucia, Queensland, Australia.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Mobli
authors.affiliation: Australian Synchrotron, Clayton, Victoria, Australia.
authors.forename: Nathan P
authors.initials: NP
authors.lastname: Cowieson
authors.affiliation: Department of Biochemistry, La Trobe University, Bundoora, Victoria, Australia.
authors.forename: Robin F
authors.initials: RF
authors.lastname: Anders
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Jamie S
authors.initials: JS
authors.lastname: Simpson
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Sheena
authors.initials: S
authors.lastname: McGowan
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia; Australian Research Council Centre of Excellence for Coherent X-ray Science, Monash University, Parkville, Victoria, Australia.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Scanlon
mesh_terms: D000953:Antigens, Protozoan / Q000737:chemistry* / Q000235:genetics; D018360:Crystallography, X-Ray; D006790:Host-Parasite Interactions; D006801:Humans; D016778:Malaria, Falciparum / Q000235:genetics / Q000469:parasitology*; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics; D010455:Peptides / Q000737:chemistry*; D010963:Plasmodium falciparum / Q000737:chemistry*; D011485:Protein Binding; D015800:Protozoan Proteins / Q000737:chemistry* / Q000235:genetics; D053838:Scattering, Small Angle; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism
chemical_list: D000953:Antigens, Protozoan; D008565:Membrane Proteins; D010455:Peptides; D015800:Protozoan Proteins; D054852:Small Molecule Libraries; C090077:apical membrane antigen I, Plasmodium