|3-D structure of virus protein suggests new approach for drug design|
November 10, 2000
Researchers have determined the 3-dimensional structure of a critical protein that allows the family of viruses causing pneumonia, bronchitis and other respiratory diseases in children to infect a cell. The structure of this protein will be particularly useful for designing drugs that can prevent viral infection.
The protein, hemagglutinin-neuraminidase (HN), sits on the outer surface of the virus and enables it to recognize, grab and enter the cell. HN's other function is to modify new virus particles before they burst out of an infected cell.
The key feature of the HN protein is that the two essential functions of this proteintargeting and entry, and exitall occur within the same tiny region, says Allen Portner, of St Jude Children's Research Hospital, in Memphis, Tennessee. The implication is that a single drug that blocks this region would prevent a virus from infecting a cell and block new viruses from leaving an infected cell to infect innocent bystanders.
If researchers solve one HN structure, they will have the framework for all of them, as all HN proteins have basically the same architecture. Previous studies have shown that antibodies that block the HN protein can block viral infection, says Portner. Understanding a protein's structure offers drug designers the opportunity to tailor a molecule that can mimic an antibody and attach to a specific nook of the HN protein.
"This report is the most exciting discovery in the field in quite some time," Fran Rubin, of the National Institute of Allergy and Infectious Diseases, is quoted as saying. There are currently no effective drugs or vaccines available for members of the paramyxovirus family of parainfluenza viruses that cause respiratory infections in 95 percent of all children before age 5.
Finding a version of the HN protein that lends itself to crystallization took nine years, says Portner, whose early efforts were unsuccessful. After many years experimenting with different viruses, the HN protein from the Newcastle Disease Virus, that causes a particularly deadly infection in birds, was first crystallized in his laboratory. All the HN proteins from these different viruses are remarkably similar, but just a few different amino acids can effect a protein's ability to form crystals, says Portner.
The actual structure of HN was determined using X-ray diffraction crystallography by Garry Taylor, of the University of Bath, in the UK. It is very difficult to predict how a sequence of amino acids, the building blocks of protein, will fold to form a functional protein. X-ray diffraction crystallography is a method for taking a photograph of the protein with almost atomic level resolution. Taylor blasts the HN crystal, which was produced in Portner's laboratory, with X-rays that bounce off at various angles and hit a photographic plate. The dots produced by the X-rays reveal how the amino acids are arranged in space.
Portner and Taylor intend to continue structure studies on HN to understand how the HN protein is able to switch between its role of attaching to proteins on the target cells and its neuraminidase function that modifies new virus particles.
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