Purdue finding may snuff out the snifflesWEST LAFAYETTE, Ind. -- Purdue University scientists have unlocked the secrets of a receptor that the common cold virus uses as an entryway to infect human cells.
A research team led by Purdue researcher Michael G. Rossmann reports that it has analyzed in atomic detail the three-dimensional structure of the part of the cellular receptor that binds to a virus that causes the majority of colds in humans.
Knowing the structure of this receptor will help scientists unravel the mystery of how cold viruses enter cells, and it may suggest ways for developing drugs that prevent the common cold and other illnesses caused by similar viral pathogens, says Rossmann, who is the Hanley Distinguished Professor of Biological Sciences.
"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," he says.
The receptor, called ICAM-1, is made up of a single protein and is shaped somewhat like an arm divided into five sections, or domains, extending from a shoulder that penetrates the cellular membrane. Rossmann's group has 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.
Similar results were found by a group directed by Tim Springer at Harvard Medical School, and they appear in the same issue of the journal.
ICAM-1 -- an acronym for intercellular adhesion molecule one -- is one of many types of adhesion molecules found in multicelled organisms. As the name implies, adhesion molecules play a role in binding cells to other molecules or cells. ICAM-1 normally functions to hold infection-fighting white blood cells in place in regions of the body that have been injured or damaged.
But somehow, a resourceful family of viruses known as rhinoviruses has developed a back-door way to use this receptor to enter human cells.
The Purdue study shows that the rhinovirus bypasses the structure that 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."
The fact that the virus attaches to a different site than the one used by white blood cells bodes well for developing ways to block the interaction, Bella says.
"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," he says.
However, such an advancement would not eliminate all colds. Rhinovirus 16, the cold virus used in the study, comes from a virus family that causes up to 70 percent of colds in humans. The remaining 30 percent of colds are caused by viruses that use other means of infecting cells, Bella says.
Rossmann's study was funded by the National Institutes of Health and the National Science Foundation. In addition, he received funding from the Lucille P. Markey Foundation.
Sources: Michael G. Rossmann, (765) 494-4911; e-mail, firstname.lastname@example.org
Jordi Bella, (765) 494-4507; e-mail, email@example.com
Writer: Susan Gaidos, (765) 494-2081; e-mail,
Purdue News Service: (765) 494-2096; e-mail, firstname.lastname@example.org
NOTE TO JOURNALISTS: A copy of the journal article and background information on X-ray crystallography are available.
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The Structure of the Two Amino-terminal Domains
How it Functions as a Rhinovirus Receptor
and as an LFA-1 Integrin Ligand
Jordi Bella, Prasanna R. Kolatkar, Christopher Marlor,
Jeffrey M. Greve and Michael G. Rossmann
The three-dimensional atomic structure of the two amino-terminal domains (D1 and D2) of ICAM-1 has been determined to 2.2 angstrom resolution and fitted into a cryo-electron microscopy reconstruction of a rhinovirus ICAM-1 complex. Rhinovirus attachment is confined to the BC, CD, DE and FG loops of the amino-terminal immunoglobulin-like domain (D1) at the end distal to the cellular membrane. The loops are structurally considerably different to those of human ICAM-2 or murine ICAM-1 which do not bind rhinoviruses. There are extensive charge interactions between ICAM-1 and human rhinoviruses, which are mostly conserved in both major and minor receptor groups of rhinoviruses.
The interaction of ICAMs with LFA-1 is known to be mediated by a divalent cation bound to the I-(insertion) domain of the alpha chain of LFA-1 and the carboxy group of a conserved glutamic acid residue on ICAMs. Domain D1 has been docked by the known structure of the I-domain. The resultant model is consistent with mutational data and provides a structural framework for the adhesion between these molecules.