To identify weak points of ZEBRA as potential drug targets Morand and Carlo Petosa from Mller's group created a high-resolution map of the protein's structure. Using the unique technology "platforms" that EMBL and the IVMS have set up in partnership with the neighbouring institutes, they obtained crystals of ZEBRA.
Examining these crystals with high-intensity X-rays at the European Synchrotron Radiation Facility (ESRF) in Grenoble, the scientists found that ZEBRA binds to DNA in a complex of two molecules. A detailed map of the interface between the two ZEBRA molecules revealed that one copy of ZEBRA plugs a large side chain into a deep pocket in the other. "This is an ideal type of structure to try to target with a drug," Petosa says. "If we can find a molecule to block access to the cavity, the copies wouldn't be able to bind to each other and dock onto DNA."
Morand and his colleagues carried out a close study of the pocket, which gave them good idea of what a "plug" would have to look like. The next step will be to screen likely molecules in hopes of finding an inhibitor. "We have been trying to develop an effective way to treat EBV infections for over 20 years, without major successes," Morand says. "Thanks to this partnership between medical research and structural biology that has grown on the Grenoble Polygone Scientifique campus, we are closer than ever before."