title: Structure and dynamics of apical membrane antigen 1 from Plasmodium falciparum FVO.
abstract: 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.
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, Victoria 3052, Australia.
authors.forename: San Sui
authors.initials: SS
authors.lastname: Lim
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.forename: Bankala
authors.initials: B
authors.lastname: Krishnarjuna
authors.forename: Komagal
authors.initials: K
authors.lastname: Kannan Sivaraman
authors.forename: Indu R
authors.initials: IR
authors.lastname: Chandrashekaran
authors.forename: Itamar
authors.initials: I
authors.lastname: Kass
authors.forename: Christopher A
authors.initials: CA
authors.lastname: MacRaild
authors.forename: Shane M
authors.initials: SM
authors.lastname: Devine
authors.forename: Cael O
authors.initials: CO
authors.lastname: Debono
authors.forename: Robin F
authors.initials: RF
authors.lastname: Anders
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Scanlon
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scammells
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.forename: Sheena
authors.initials: S
authors.lastname: McGowan
mesh_terms: D000953:Antigens, Protozoan / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D016778:Malaria, Falciparum / Q000469:parasitology*; D008565:Membrane Proteins / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D010963:Plasmodium falciparum / Q000737:chemistry*; D010966:Plasmodium vivax / Q000737:chemistry; D017434:Protein Structure, Tertiary; D015800:Protozoan Proteins / Q000737:chemistry*
chemical_list: D000953:Antigens, Protozoan; D008565:Membrane Proteins; D015800:Protozoan Proteins; C090077:apical membrane antigen I, Plasmodium