Antimalarial Activity of Cupredoxins THE INTERACTION OF PLASMODIUM MEROZOITE SURFACE PROTEIN 1(19) (MSP1(19)) AND RUSTICYANIN

作者:Cruz Gallardo Isabel; Diaz Moreno Irene; Diaz Quintana Antonio; Donaire Antonio; Velazquez Campoy Adrian; Curd Rachel D; Rangachari Kaveri; Birdsall Berry; Ramos Andres; Holder Anthony A; De la Rosa Miguel A*
来源:Journal of Biological Chemistry, 2013, 288(29): 20896-20907.
DOI:10.1074/jbc.M113.460162

摘要

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 (MSP1(19)) 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, MSP1(19) 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 MSP1(19)-cupredoxin complexes. Among the cupredoxins tested, rusticyanin forms a well defined complex with MSP1(19) 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.