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Molecular research suggests
shift needed in how drugs are created
Life Sciences Editor
photo to enlarge
by Kwame Ross
by Satish K. Nair (left), a U. of I. professor of biochemistry , and Michael V. Lasker, an M.D./Ph.D.
student in the UI College of Medicine, has given scientists
the first close-up look at a pro-inflammatory signaling
molecule involved in immune response in mammals. The
discovery may impact drug development.
— 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
Since researchers at the University 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
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,”
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.
Mark M. Gajjar, an undergraduate student who now works in the department
of biochemistry and molecular biology at the University of Chicago,
also was a co-author.
The research was supported through start-up funds to Nair from the Institute
for Genomic Biology at Illinois. Lasker was funded by a National
Institutes of Health National Research Service Award from the NIH Institute
of Neurological Disorders and Stroke.