Respiratory infections strike millions of people each year and collectively
cause more deaths than any single infectious disease. For the first time,
scientists have determined the structure of a key protein from a
paramyxovirus, a leading cause of respiratory disease in children throughout
the world. In the November issue of Nature Structural Biology, researchers
describe the three-dimensional structure of a protein used by
paramyxoviruses to latch onto, penetrate and exit the cells of the
respiratory tract. Their study reveals clues for effective new drugs and
highlights the benefits of structural biology in helping guide drug design
against communicable diseases.
Paramyxoviruses cause several respiratory diseases in humans and animals.
One of these viruses, parainfluenza, infects almost all children before they
reach the age of 5, causing illnesses ranging from colds to pneumonia.
"This report is the most exciting discovery in the field in quite some
time," says Fran Rubin, Ph.D., program officer for respiratory diseases at
the National Institute of Allergy and Infectious Diseases (NIAID), which
partially funded the study. "We have no vaccines or effective drugs to stop
viruses like parainfluenza. This study opens new possibilities for drug
The study focuses on a protein called hemagglutinin-neuraminidase (HN),
which is found on the surface of many paramyxoviruses. The protein plays a
key role in infection, helping the virus recognize and enter cells and to
spread to neighboring cells as the virus reproduces. Each of these
properties depends on the unique shape of the protein and the chemical
charges distributed across its surface.
Scientists have studied the design of similar proteins to develop effective
drugs against other viruses, but the three-dimensional structure of
paramyxovirus HN has remained unknown because researchers have been unable
to "grow" these proteins into the crystals required for study. This has
thwarted efforts to design new drugs that specifically attack the molecule.
The researchers in this study, led by Allen Portner, Ph.D., of St. Jude
Children's Research Hospital in Memphis, Tenn., and Garry Taylor, Ph.D., of
St. Andrews University in Scotland, used X-rays to probe the molecular
structure of HN from Newcastle disease virus, a paramyxovirus that causes
respiratory illness in chickens. "My laboratory has tried for years to find
an HN protein that would permit us to take a look at its molecular
structure, but many would not form the crystals required to get an X-ray
picture," explains Dr. Portner. "Newcastle disease virus finally provided a
protein that solved our problems." The scientists knew from genetic and
biochemical analysis that this HN gene is very similar to the HN of other
paramyxoviruses, making their results applicable to parainfluenza and
Once they determined the HN structure, the researchers were surprised to
learn that two different virus properties attachment and release from the
cells lining the respiratory tract are controlled by the same region of
HN. Because viruses must latch onto the cell before entering, this one
region is critical for several virus functions. "What this means is we
might be able to attack multiple facets of the virus through a single site,"
explains Dr. Taylor. "If we can design a molecule that blocks this site, we
might have a drug that prevents all three key steps in virus infection -
attachment, cell entry and release."
As Dr. Portner states, "This study offers hope that we will one day be able
to treat the infection before the damage is done, improving the health of
many children and beating back a leading respiratory infectious disease."