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Molecular research suggest shift needed in how some drugs are created

The first close-up look at a pro-inflammatory signaling molecule involved in immune response in mammals suggests that researchers "should rethink what they are doing" in creating drugs based on a fruit-fly model, scientists say.

Reporting in the Oct. 1 issue of the Journal of Immunology, researchers at the University of Illinois at Urbana-Champaign unveiled the crystal structure of mouse interleukin-1 receptor-associated kinase-4 (IRAK-4).

They found a distinct highly structured loop between two helices that is remarkably different from that found in Pelle, an IRAK-4-like "death-domain" protein from Drosophila melanogaster that was determined nearly a decade ago. The death domain is so-named because of a resemblance to proteins that are involved in programmed cell death.

"It has been thought in the field that a death domain is a death domain, and molecular recognition takes place in the same fashion," said lead author Michael V. Lasker, an M.D./Ph.D. student in the College of Medicine at Urbana-Champaign. "But the crystal structure of our death domain clearly shows that indeed this is not the case."

The crystal structure of IRAK-4, as was the case for Pelle, was determined by X-ray crystallography. Using this technique, X-rays are directed into molecules of IRAK-4 that have been coaxed to form crystals. The diffraction data from the experiments allow the structure to be visualized down to angstrom-level resolution (one hundred-millionth of a centimeter). The structure of IRAK-4 was determined to a resolution of 1.7 angstroms.

The molecules in question are part of innate immune systems -- an inherent immune response coded by DNA in all living things -- that are crucial for survival against pathogens such as bacteria and fungi. Deficiencies in the system or an over-active response can set the stage for various infections, septic shock and numerous autoimmune disorders.

Since researchers at the University of Texas Southwes
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Source:University of Illinois at Urbana-Champaign


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