title: Structure of the malaria vaccine candidate antigen CyRPA and its complex with a parasite invasion inhibitory antibody.
abstract: Invasion of erythrocytes byPlasmodialmerozoites is a composite process involving the interplay of several proteins. Among them, thePlasmodium falciparumCysteine-Rich Protective Antigen (PfCyRPA) is a crucial component of a ternary complex, including Reticulocyte binding-like Homologous protein 5 (PfRH5) and the RH5-interacting protein (PfRipr), essential for erythrocyte invasion. Here, we present the crystal structures of PfCyRPA and its complex with the antigen-binding fragment of a parasite growth inhibitory antibody. PfCyRPA adopts a 6-bladed β-propeller structure with similarity to the classic sialidase fold, but it has no sialidase activity and fulfills a purely non-enzymatic function. Characterization of the epitope recognized by protective antibodies may facilitate design of peptidomimetics to focus vaccine responses on protective epitopes. Both in vitro and in vivo anti-PfCyRPA and anti-PfRH5 antibodies showed more potent parasite growth inhibitory activity in combination than on their own, supporting a combined delivery of PfCyRPA and PfRH5 in vaccines.
authors.affiliation: Medical Parasitology and Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Paola
authors.identifier: 0000-0002-1394-927X
authors.initials: P
authors.lastname: Favuzza
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Guffart
authors.affiliation: Medical Parasitology and Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Tamborrini
authors.affiliation: Medical Parasitology and Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Bianca
authors.initials: B
authors.lastname: Scherer
authors.affiliation: Medical Parasitology and Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Anita M
authors.initials: AM
authors.lastname: Dreyer
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Arne C
authors.initials: AC
authors.lastname: Rufer
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Erny
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Joerg
authors.initials: J
authors.lastname: Hoernschemeyer
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Ralf
authors.initials: R
authors.lastname: Thoma
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Georg
authors.initials: G
authors.lastname: Schmid
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Bernard
authors.initials: B
authors.lastname: Gsell
authors.affiliation: Medical Parasitology and Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Araceli
authors.initials: A
authors.lastname: Lamelas
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Joerg
authors.initials: J
authors.lastname: Benz
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Joseph
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Hugues
authors.initials: H
authors.lastname: Matile
authors.affiliation: Medical Parasitology and Infection Biology Department, Swiss Tropical and Public Health Institute, Basel, Switzerland.|University of Basel, Basel, Switzerland.
authors.forename: Gerd
authors.identifier: 0000-0003-1957-2925
authors.initials: G
authors.lastname: Pluschke
authors.affiliation: Roche Pharmaceutical Research and Early Development, Small Molecule Research, Roche Innovation Center Basel, F Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: Markus G
authors.initials: MG
authors.lastname: Rudolph
mesh_terms: D000913:Antibodies, Protozoan / Q000737:chemistry* / Q000378:metabolism*; D000953:Antigens, Protozoan / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D017780:Malaria Vaccines / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D015800:Protozoan Proteins / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D000913:Antibodies, Protozoan; D000953:Antigens, Protozoan; C000622047:CyRPA protein, Plasmodium falciparum; D017780:Malaria Vaccines; D015800:Protozoan Proteins
keywords: <i>p. falciparum</i>; CyRPA; Malaria vaccine candidate; biophysics; crystal structure; infectious disease; invasion inhibitory antibody; microbiology; sialidase; structural biology; β-propeller