Crystal Structure of Key Ebolavirus Protein Reported

A team of molecular biologists has solved the structure of an Ebolavirus protein that may be responsible for the ability of the virus to invade and infect mammalian cells.

Investigators at Iowa State University (Ames, USA) used a combination of X-ray crystallography and nucleic magnetic resonance spectroscopy (NMR) to solve the structure of a noninfectious sample of the Ebola VP35 protein. This protein plays several roles in the viral metabolism, acting as a component of the viral RNA polymerase complex, a viral assembly factor, and an inhibitor of host interferon (IFN) production. Mutation of select basic residues within the C-terminal half of VP35 eliminates its ability to bind double stranded RNA (dsRNA), impairs VP35-mediated IFN antagonism, and slows growth of the virus in vitro and in vivo.


Results published in the January 2, 2009 online edition of the journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) revealed that at a resolution of 1.4 Angstroms VP35 formed a unique fold. In this fold resided two basic residue clusters, one of which was important for dsRNA binding. The dsRNA-binding cluster was centered on Arg-312 (arginine-312), a highly conserved residue required for IFN inhibition. Mutation of residues within this cluster significantly changed the surface electrostatic potential and diminished dsRNA-binding activity.

"Usually when viruses infect cells, the host immune system can fight to eventually clear the virus. But with Ebola infections, the ability of the host to mount a defense against the invading virus is lost," said senior author Dr. Gaya Amarasinghe, assistant professor in biochemistry, biophysics, and molecular biology at Iowa State University. "The next step is to use this structure to identify and design drugs that potentially bind with VP35. Without functional VP35, the Ebolavirus cannot replicate so it is noninfectious."

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