Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Molecular research suggests shift needed in how some drugs are created

05.10.2005


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 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.

Jim Barlow | EurekAlert!
Further information:
http://www.uiuc.edu

More articles from Life Sciences:

nachricht A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

A Map of the Cell’s Power Station

18.08.2017 | Life Sciences

Engineering team images tiny quasicrystals as they form

18.08.2017 | Physics and Astronomy

Researchers printed graphene-like materials with inkjet

18.08.2017 | Materials Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>