title: Antimalarial activity of cupredoxins: the interaction of Plasmodium merozoite surface protein 119 (MSP119) and rusticyanin.
abstract: The discovery of effective new antimalarial agents is urgently needed. One of the most frequently studied molecules anchored to the parasite surface is the merozoite surface protein-1 (MSP1). At red blood cell invasion MSP1 is proteolytically processed, and the 19-kDa C-terminal fragment (MSP119) remains on the surface and is taken into the red blood cell, where it is transferred to the food vacuole and persists until the end of the intracellular cycle. Because a number of specific antibodies inhibit erythrocyte invasion and parasite growth, MSP119 is therefore a promising target against malaria. Given the structural homology of cupredoxins with the Fab domain of monoclonal antibodies, an approach combining NMR and isothermal titration calorimetry (ITC) measurements with docking calculations based on BiGGER is employed on MSP119-cupredoxin complexes. Among the cupredoxins tested, rusticyanin forms a well defined complex with MSP119 at a site that overlaps with the surface recognized by the inhibitory antibodies. The addition of holo-rusticyanin to infected cells results in parasitemia inhibition, but negligible effects on parasite growth can be observed for apo-rusticyanin and other proteins of the cupredoxin family. These findings point to rusticyanin as an excellent therapeutic tool for malaria treatment and provide valuable information for drug design.
authors.affiliation: From the Instituto de Bioquímica Vegetal y Fotosíntesis (IBVF), cicCartuja, Universidad de Sevilla-CSIC, Avenida Américo Vespucio 49, Sevilla 41092, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Cruz-Gallardo
authors.affiliation: From the Instituto de Bioquímica Vegetal y Fotosíntesis (IBVF), cicCartuja, Universidad de Sevilla-CSIC, Avenida Américo Vespucio 49, Sevilla 41092, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Díaz-Moreno
authors.affiliation: From the Instituto de Bioquímica Vegetal y Fotosíntesis (IBVF), cicCartuja, Universidad de Sevilla-CSIC, Avenida Américo Vespucio 49, Sevilla 41092, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Díaz-Quintana
authors.affiliation: the Departamento de Química Inorgánica, Facultad de Química, Universidad de Murcia, Campus Universitario de Espinardo, Murcia 30100, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Donaire
authors.affiliation: the Instituto de Biocomputación y Física de Sistemas complejos (BIFI), Universidad de Zaragoza, c/Mariano Esquillor, Zaragoza 50018, Spain.
authors.forename: Adrián
authors.initials: A
authors.lastname: Velázquez-Campoy
authors.affiliation: the Parasitology Division and.
authors.forename: Rachel D
authors.initials: RD
authors.lastname: Curd
authors.affiliation: the Parasitology Division and.
authors.forename: Kaveri
authors.initials: K
authors.lastname: Rangachari
authors.affiliation: Molecular Structure Division, Medical Research Council (MRC) National Institute for Medical Research, The Ridgeway, Mill Hill, London W7 1AA, United Kingdom.
authors.forename: Berry
authors.initials: B
authors.lastname: Birdsall
authors.affiliation: Molecular Structure Division, Medical Research Council (MRC) National Institute for Medical Research, The Ridgeway, Mill Hill, London W7 1AA, United Kingdom.
authors.forename: Andres
authors.initials: A
authors.lastname: Ramos
authors.affiliation: the Parasitology Division and.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Holder
authors.affiliation: From the Instituto de Bioquímica Vegetal y Fotosíntesis (IBVF), cicCartuja, Universidad de Sevilla-CSIC, Avenida Américo Vespucio 49, Sevilla 41092, Spain,. Electronic address: marosa@us.es.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: De la Rosa
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000737:chemistry; D000962:Antimalarials / Q000494:pharmacology*; D001059:Apoproteins / Q000378:metabolism; D001400:Azurin / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002151:Calorimetry; D017124:Conserved Sequence; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D020066:Merozoite Surface Protein 1 / Q000737:chemistry / Q000378:metabolism*; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects / Q000254:growth & development; D010967:Plasmodium yoelii / Q000187:drug effects / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D016415:Sequence Alignment; D012984:Software; D013816:Thermodynamics
chemical_list: D000911:Antibodies, Monoclonal; D000962:Antimalarials; D001059:Apoproteins; D007140:Immunoglobulin Fab Fragments; D020066:Merozoite Surface Protein 1; C050107:cupredoxin; C012543:rusticyanin; D001400:Azurin
keywords: Docking; Isothermal Titration Calorimetry; MSP119; Malaria; NMR; Plasmodium; Rusticyanin