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: Isabel Cruz-Gallardo, Irene Díaz-Moreno, Antonio Díaz-Quintana, Antonio Donaire, Adrián Velázquez-Campoy, Rachel D Curd, Kaveri Rangachari, Berry Birdsall, Andres Ramos, Anthony A Holder, Miguel A De la Rosa
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 288 Issue 29 Pg. 20896-20907 (Jul 19 2013) ISSN: 1083-351X [Electronic] United States
• PMID: 23749994 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antimalarials
• Apoproteins
• Immunoglobulin Fab Fragments
• Merozoite Surface Protein 1
• cupredoxin
• rusticyanin
• Azurin

Topics

• Amino Acid Motifs
• Amino Acid Sequence
• Antibodies, Monoclonal (chemistry)
• Antimalarials (pharmacology)
• Apoproteins (metabolism)
• Azurin (chemistry, metabolism, pharmacology)
• Calorimetry
• Conserved Sequence
• Immunoglobulin Fab Fragments (chemistry)
• Magnetic Resonance Spectroscopy
• Merozoite Surface Protein 1 (chemistry, metabolism)
• Molecular Docking Simulation
• Molecular Sequence Data
• Oxidation-Reduction (drug effects)
• Plasmodium falciparum (drug effects, growth & development)
• Plasmodium yoelii (drug effects, metabolism)
• Protein Binding (drug effects)
• Sequence Alignment
• Software
• Thermodynamics