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Molecular Structure Key To Allergies And Asthma Is Identified

Date:
July 20, 2000
Source:
Northwestern University
Summary:
In a breakthrough that could affect the more than 50 million Americans who suffer from allergies and asthma, researchers at Northwestern University and Harvard Medical School have identified the structure of the interaction complex of two molecules that are central to the allergic response in humans.

EVANSTON, Ill. -- In a breakthrough that could affect the more than 50 million Americans who suffer from allergies and asthma, researchers at Northwestern University and Harvard Medical School have identified the structure of the interaction complex of two molecules that are central to the allergic response in humans.

The discovery of how the antibody binds to the mast cell receptor could lead to the development of a new class of drugs that attack allergies at their source, preventing the cascade of released chemicals that leads to the itching, sneezing and congestion of allergies, the life-threatening respiratory distress of asthma and anaphylactic shock. Todayís commercial drugs only treat symptoms once the allergic response is already under way.

The findings, which will be published July 20 in the journal Nature, also may lead to novel treatments for autoimmune disorders and improved cancer therapies based on antibodies.

The researchers determined the structure by imaging crystals of the molecular complex of the antibody immunoglobin-E (IgE) and its high-affinity receptor, using the extremely brilliant X-rays produced by the Advanced Photon Source (APS) synchrotron at Argonne National Laboratory in Illinois.

"In order to design drugs effectively, a chemist needs to know the structure and shape of the target molecules," said Theodore S. Jardetzky, the Northwestern X-ray crystallographer who led the study. "Our discovery provides a three-dimensional image of how the two molecules interact, showing where and how the antibody binds to the receptor. This is valuable information in the world of drug design."

Antibodies in the human immune system act as antennas for antigens, molecules foreign to the body, and attach to antibody receptors on the surface of immune system cells. When antigens are detected, the antibodies activate the cells. Once triggered, the cells respond by unleashing a barrage of immune system defense mechanisms.

In allergy and asthma, the high-affinity immunoglobin-E receptor on the surface of mast cells anchors IgE, the antibody that recognizes allergens and triggers the mast cells to produce histamine, leukotrienes, cytokines and other broadly-acting effector substances, causing symptoms that range from mildly annoying to life-threatening.

Jardetzky likens the interaction between receptor and antibody to a lock and key. "The antibody is the key that fits into the lock of the receptor on the mast cell. When an allergen, say a molecule present in cat dander, attaches to the antibody, it provides the signal to turn the key. Thatís when the mast cell unleashes the chemicals that create such havoc in the body."

The importance of the researchersí discovery lies in knowing how the "lock" and "key" interact with each other. Jardetzky and his colleagues determined that the IgE antibody binds in two places on the receptor, and that, because of its shape, the antibody may make a better target for drug therapies than the receptor.

"The idea is to design molecules that would prevent IgE from binding to the receptor," said Jardetzky, who is assistant professor of biochemistry, molecular biology and cell biology. "Now that we know the structures of the antibody and receptor, we believe that it would be easier to find inhibitor molecules that attach to the antibody, thereby preventing the key from fitting into the lock."

The gene for the IgE receptor was cloned 14 years ago by Jardetzkyís collaborator, Jean-Pierre Kinet, professor of pathology at Harvard Medical School and director of the Laboratory of Allergy and Immunology at Beth Israel Deaconess Medical Center.

"I have been waiting for this moment for 15 years," said Kinet. "The crystals and the structures they show us are fantastic.

"With the antibody-receptor structure in hand, finding a new drug that can be taken orally to inhibit IgE is a definite possibility. Current anti-IgE therapies, used in the most severe cases of allergies and asthma, involve the injection of antibodies into the bloodstream once or twice a month. This is not a viable treatment for people who suffer, for example, from hayfever."

Jardetzky credits the very high intensity X-rays at the DuPont-Northwestern-Dow beamline at the APS for enabling the researchers to image the structure at 3.5 angstroms. An angstrom is one ten-billionth of a meter, or about one-hundred-millionth of an inch. These dimensions are about 100,000 times smaller than a cell or 100 to 1,000 times smaller than a virus. This resolution was critical for an accurate picture of how the 5,000 atoms in the antibody-receptor structure are assembled.

Because they are so small, the antibody and receptor molecules could not be imaged directly. Instead, the researchers used many of these molecules to create a crystal that could be imaged. Using the method of X-ray diffraction, they bombarded the crystal with X-rays, which bounced off the atoms within the crystal. By collecting and analyzing this information, Jardetzky and his colleagues determined the location of each atom within the structure.

"The solving of this difficult structure comes at a critical time because the prevalence of allergies and asthma is on the rise in more developed countries," said Jardetzky.

In addition to Jardetzky and Kinet, other authors on the paper are Scott C. Garman, Beth A. Wurzburg and Svetlana S. Tarchevskaya, from Northwestern.

The research was supported by the National Institutes of Health, the Pew Scholars Program in the Biomedical Sciences, Heska Corporation and the American Cancer Society.


Story Source:

The above story is based on materials provided by Northwestern University. Note: Materials may be edited for content and length.


Cite This Page:

Northwestern University. "Molecular Structure Key To Allergies And Asthma Is Identified." ScienceDaily. ScienceDaily, 20 July 2000. <www.sciencedaily.com/releases/2000/07/000720080816.htm>.
Northwestern University. (2000, July 20). Molecular Structure Key To Allergies And Asthma Is Identified. ScienceDaily. Retrieved September 2, 2014 from www.sciencedaily.com/releases/2000/07/000720080816.htm
Northwestern University. "Molecular Structure Key To Allergies And Asthma Is Identified." ScienceDaily. www.sciencedaily.com/releases/2000/07/000720080816.htm (accessed September 2, 2014).

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