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Key Asthma And Allergy Molecule Pictured

December 23, 1998
Northwestern University
In a finding that is expected to lead to the development of a new class of drugs for allergy and asthma sufferers, researchers at Northwestern University and Harvard Medical School have determined the precise shape of the receptor molecule that triggers the allergic response in the immune system.

In a finding that is expected to lead to the development of a new class of drugs for allergy and asthma sufferers, researchers at Northwestern University and Harvard Medical School have determined the precise shape of the receptor molecule that triggers the allergic response in the immune system.

The finding, reported in the Dec. 23 issue of the journal Cell, is the first structure reported for a member of this family of antibody receptor proteins. It was made by probing crystals of the receptor called the high-affinity immunoglobulin-E receptor with the extremely brilliant X-rays produced by the Advanced Photon Source synchrotron at Argonne National Laboratory in Illinois.

"We think this identifies the structure that all of the members of this antibody receptor family will have," says Theodore S. Jardetzky, the Northwestern X-ray crystallographer who led the study.

As a class, antibody receptors allow immune system cells to affix antibodies onto the cells' surface to act as antennas for antigens, or foreign triggering substances. When so triggered, the cells respond by unleashing a barrage of immune responses. In the case of allergy and asthma, the high-affinity immunoglobulin-E receptor on the surface of mast cells anchors immunoglobulin-E, an antibody that receives allergens and triggers the mast cells to produce histamine, leukotrienes and other broadly-acting effector substances that lead to the itching, sneezing and congestion of allergies -- and the life-threatening respiratory distress of asthma and anaphylactic shock.

Other members of the antibody receptor family are involved in tumor recognition, autoimmune diseases such as arthritis, and in normal immunity.

The IG-E receptor was of particular interest because an estimated 20 percent of the population suffers from allergies. Asthma afflicts 15 million people in the U.S. and causes 500,000 hospitalizations and 5,000 deaths each year. The National Institutes of Health estimate that direct and indirect monetary costs related to asthma will total $11.3 billion in 1998.

Current treatments are aimed at blocking the action of the signal molecules or the inflammation they cause. But knocking out the master switch would in principle be more effective than trying to impede all the signals the mast cell sends out, said Jardetzky, who is assistant professor of biochemistry, molecular biology and cell biology.

"The mast cells can release many different types of compounds," Jardetzky said. "Antihistamines and antileukotriene drugs each block only one part of the response that the receptor is triggering. If we could find a drug that blocked the receptor from binding the antibody, the cell would never release any of those compounds because it would never know a triggering allergen was present."

The gene for the IG-E receptor was cloned 12 years ago by Jardetzky's collaborator, Jean-Pierre Kinet, professor of pathology and director of the Laboratory of Allergy and Immunology at Harvard Medical School.

"When we cloned the receptor, we hoped we could start developing agents to target the receptor," Kinet said. "It is such a central molecule, it has been given a lot of attention by the pharmaceutical industry because it is a very good target for therapy. But there is absolutely nothing commercially available right now that hits that target.

"With the solving of the structure, now we have the opportunity to derive information which could help in the design of molecules which could inhibit IG-E binding."

Several pharmaceutical and academic teams had been trying to study the receptor by expressing its gene in cultured cells. But the receptor protein that researchers obtained from these cells had stubbornly defied all attempts to solve the crystal structure.

Cells "decorate" the IG-E receptor protein molecule by attaching sugars to it, Jardetzky explained, which makes crystallization especially difficult. He, Kinet and Northwestern research associate Scott C. Garman finally succeeded in crystallizing the receptor protein by expressing the human IG-E gene in cultured insect cells, which attach fewer sugars to the protein.

"We put the gene into many different types of cells to see if we could get a well-behaved form of the protein that would grow a good crystal," Garman said. The sugar content does not affect the biological properties of the receptor.

Jardetzky said Argonne's Advanced Photon Source was also key to the determination.

"The DuPont-Northwestern-Dow beamline at the APS not only provides very high intensity X-rays, but it makes it easy to vary the wavelength," he said. "In this way can get even more information in solving the structure."

The shape of the receptor, Jardetzky said, turned out to be "a little surprising."

"It was known the receptor was formed of two independently folded domains," Jardetzky said. "It was a surprise that the two domains are bent over each other quite dramatically. This creates a very convex binding surface for the antibody. It is a tight boomerang shape, and the antibody binds at the top of that elbow."

The resolution of the determined structure is 2.4 angstroms. An angstrom is one-ten billionth of a meter, or about one-hundred millionth of an inch -- a little less than the distance between the nuclei of two bonded atoms in a molecule.

"The high resolution allows us to go from getting just a general idea of what the protein looked like to looking at many more specific atomic interactions within the molecule, and that's important for drug design," Jardetzky said. "If you want to use these coordinates for designing something new, you have to have the most accurate picture you can get."

The research was funded by Heska Corporation, a veterinary pharmaceutical company in Fort Collins, Colo., the National Institutes of Health, the Pew Scholars Program in the Biomedical Sciences, and the American Cancer Society.

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