Washington University scientists map key malaria protein

Scientists from Washington University in St. Louis were recently able to map the structure of a key protein the malaria parasite uses to survive.

Plasmodium falciparum, the protozoan that causes the most lethal form of malaria, uses the critical protein, an enzyme known as PMT, to produce cell membrane. The parasite cannot survive without the enzyme, and though it appears similar to those used by other organisms, it is unique to P. falciparum, making it a potential target for new antimalarial drugs, according to

It took nearly six years for Dr. Joseph Jez, a professor of biology in the Arts & Sciences department, and his team to complete their work, which was published in The Journal of Biological Chemistry and featured in the ASBMB Today, the newsletter of the American Society for Molecular Biology.

"What my lab does is crystallize proteins so that we can see what they look like in three dimensions," Jez said, reports. "The idea is that if we know a protein's structure, it will be easier to design chemicals that would target the protein's active site and shut it down."

Jez considers the latest discovery to be the culmination of a project he began when he was working at the Danforth Plant Science Center in St. Louis and collaborated on with a team of scientists from the biotech company Divergence.

"At the time, C. elegans had just been sequenced and the Divergence scientists were looking at using it as an easy model to work out the biochemistry of parasitic nematodes," Jez said, according to “The plan was to try to grow better crystals of the C. elegans protein, ones good enough to get readable X-ray diffraction patterns.”

Years later, the crystals looked better, but were still not as good as Jez had hoped. Jez suggested that a colleague, Soon Goo Lee, look at homolgous proteins found in other organisms.

“Lee went from working with two C. elegans proteins to three plant proteins, two other nematode proteins and then the Plasmodium protein,” Jez said, according to

After working through a series of technically and computationally demanding issues, the pair managed to obtain four crystallized P. falciparum enzymes that they could examine under an X-ray beam at Argonne National Laboratory in Chicago.

"I never thought it would work, but we took them to Argonne anyway and he actually did surgery under the microscope and cracked off a little tiny piece of it,” Jez said, reports. “Once we had a Plasmodium crystal that was diffracting really well, we could try back-calculating to see whether we could extract the atom positions from the data.

"When you see a map like that, it's like suddenly the wind has kicked up and you're sailing free, because there's this moment, like, before you click that button, no one has ever seen how this protein is put together in three dimensions. You're the first person to ever see it. The irony of it is we got such good quality diffraction pattern and electron density maps off such an ugly crystal."

Jez plans to continue analyzing how the enzyme works, and, potentially, how it can be disabled. New antimalarials are critically needed and the protein is an ideal, and now less mysterious, target.