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Molecular research suggests shift needed in how some drugs are created

of Texas Southwestern in Dallas and the Howard Hughes Medical Institute reported the structure of Pelle bound to the adapter molecule known as Tube, there has been an effort to target the similar IRAK-4 molecule in mammals, said Satish K. Nair, a U. of I. professor of biochemistry.

The Pelle-Tube complex plays a crucial role in the innate immune response of fruit flies to fungal infection. IRAK-4 plays a similar role in humans and animals.

The hope is that drugs can be developed to target the molecule-binding pathway, which would be beneficial for treating arthritis and reducing inflammation, said Nair, who also is a researcher in the Center for Biophysics and Computational Biology at Illinois. Signaling in the pathway uses protein molecules that contain death-domains.

"What our structure tells us is that the particular arrangement that was seen in the structure that was solved by the researchers at Dallas Southwestern cannot possibly exist in humans, because of bad steric interactions that preclude the formation of this particular complex," Nair said.

Steric interactions refer to contacts that result when two protein molecules bind with each other. Bad interactions mean that the proteins cannot line up and connect properly. A tight connection is necessary to trigger an immune response.

A mammalian counterpart for Drosophila's Tube molecule has not been found, but Lasker and Nair theorize that adaptors that bind IRAK-4 will either bind at a different site, or the adapter molecule will have an interface that can handle IRAK-4's larger loop.

Researchers in Nair's lab already are looking at the complex's structure in humans.


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Contact: Jim Barlow, Life Sciences Editor
jebarlow@uiuc.edu
217-333-5802
University of Illinois at Urbana-Champaign
3-Oct-2005


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