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Malaria mechanism revealed

By determining the molecular structure of a protein that enables malaria parasites to invade red blood cells, researchers have uncovered valuable clues for rational antimalarial drug design and vaccine development. The findings are reported in the July 29 issue of the journal Cell.

Malaria causes approximately 400 million clinical cases and 2 million deaths annually, with more than 80% of deaths occurring among children. The disease is caused by mosquito-borne parasites of the genus Plasmodium (primarily Plasmodium falciparum). Following the initial stages of infection, merozoite-stage parasites ("merozoites") invade red blood cells, leading to clinical symptoms and in many cases, death.

"Niraj Tolia [the first author of the study] had malaria when he was young. So when he joined my lab as a graduate student, it didn't take long for me to convince him that this was a good project," says structural biologist Leemor Joshua-Tor of Cold Spring Harbor Laboratory, who led the research.

A major pathway through which malaria parasites invade red blood cells is the binding of a protein on the surface of merozoites called EBA-175 to a receptor protein on the surface of red blood cells called glycophorin A. Merozoites die if they do not invade red blood cells soon after their release (from liver cells) into the bloodstream. Thus, the binding of EBA-175 to glycophorin A is a prominent target for the development of therapies to control malaria.

To explore the molecular basis of the binding of EBA-175 to glycophorin A--with the rationale that such information might reveal strategies for preventing and treating malaria--the researchers used x-ray crystallography to determine the atomic structure of a key portion of the EBA-175 protein called the RII domain.

The results revealed that two molecules of RII come together in a manner resembling a handshake, and that the overall shape of such RII "dimers" resembles a donut with two holes. (Image
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Contact: Peter Sherwood
sherwood@cshl.edu
516-367-6947
Cold Spring Harbor Laboratory
28-Jul-2005


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