West Lafayette, IND (4/13/98)- The determination
of the three-dimensional structure the receptor used by the rhinovirus
could lead to the long-sought treatment for the common cold.
Researcher
Michael G. Rossmann and colleagues at Purdue University have been studying
the three-dimensional structure of ICAM-1 (intercellular adhesion molecule
one), the keyhole through which the cold virus enters human cells. Having
determined the structure of the receptor, the researchers should be able
to better understand how the cold virus infection occurs. This should lead
to the development of antiviral agents against the ancient scourge, the
rhinovirus.
Caption: The common cold
virus rhinovirus 16 contains 60 sites capable of connecting to a receptor,
called ICAM-1, on human cells.
"By solving the structure of this receptor, we can gain insights into
the chemical and biological activity that occurs when a cold virus infects
a human cell," saysRossmann, who is the Hanley Distinguished Professor
of Biological Sciences at Purdue.
The ICAM-1 receptor consists of a single protein shaped like an arm
divided into five sections, or domains, extending from a shoulder that
penetrates the cellular membrane. Using X-ray crystallography, Rossmann
and colleagues have solved the structure of the first two domains, which
are located at the "hand" end of the molecule where the virus attaches.
Each cell may contain thousands of these receptors on its membrane. Another
group at Harvard Medical School reports similar findings.
ICAM-1 is one of a number of types of adhesion molecules found in multi-celled
organisms. These adhesion molecules play a role in binding cells to other
molecules or cells. ICAM-1 normally functions tohold infection-fighting
white blood cells in place in regions of the body that have been injured
or damaged. Rhinoviruses have evolved a way of exploiting the receptor
to gain entry to human cells.
The current research reveals that the rhinovirus bypasses the structure
ICAM-1 uses to bind to white blood cells, and binds instead to another
part of the receptor to gain entry into the cell, says Jordi Bella, a postdoctoral
researcher working with Rossmann on the study.
"Our study shows that the very tip of the ICAM-1 molecule is shaped
somewhat like a hand, with a thumb
and three projections, or fingers," Bella says. "Normally, white blood
cells bind to the thumb-like projection. But the virus binds to the three
finger-like projections, and interacts with the receptor to gain entry
into the cell."
These finger-like projections are what sets ICAM-1 apart from other
cellular adhesion molecules, and they make it a perfect complement to the
rhinovirus structure, says Rossmann, who in 1986 became the first scientist
to solve the structure of a cold virus.
The finger-like projections also may distinguish human ICAM-1 from
the ICAM-1 found in all other animals,
except chimpanzees, and may explain why only humans and chimpanzees are
infected by the cold virus.
"The shell of the rhinovirus has deep crevices or canyons capable of
interacting with the finger-like projections of the ICAM-1 receptor," Rossmann
says. "The virus probably has adapted itself to be able to attach to this
particular molecule in humans, so that they fit exactly, similar to a lock
and key."
It appears that when the virus attaches to one or more receptor sites
on a cell, the cell membrane engulfs the virus, wrapping around it and
allowing it to come in contact with more receptor sites. Next, the shell
of the rhinovirus unfolds and releases its genetic material into the cell.
The researchers are encourage by the observation that the virus attaches
to a different site than the one used by white blood cells. This suggests
an approach for developing methods to block the interaction.
"If scientists could prevent that interaction from occurring, either
by a drug or genetic engineering techniques, we could eliminate a large
percentage of colds in humans without interfering with the normal function
of the ICAM-1
receptor," says Bella.
While the new findings could lead to ways to slow down rhinovirus infection,
it may not slow down the 30% of colds caused by other viruses, he added.
The research appears in the April 14, 1998 issue of the Proceedings
of the National Academy of Sciences
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