Navigation Links
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 tern 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.


'"/>

Source:University of Illinois at Urbana-Champaign


Related biology news :

1. Molecular biology fills gaps in knowledge of bat evolution
2. Molecular machine may lead to new drugs to combat human diseases
3. Molecular Motors Cooperate In Moving Cellular Cargo, Study Shows
4. Molecular models advance the fight against malaria
5. Molecular fossils uncover link between viruses and the immune system
6. Molecular thermometers on skin cells detect heat and camphor
7. Molecular messengers perform a crucial role in the ability of injured nerve cells to heal themselves
8. Molecular steps involved in the creation of gene-silencing microRNAs identified
9. Molecular miners find pain relief drugs from the sea
10. Molecular mechanism of feather formation found
11. Molecular trigger for Huntingtons disease found
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:11/30/2016)... , Nov. 30, 2016 Not many of us realize that we ... of recovery so we need to do it well. Inadequate sleep levels have been ... blood pressure, stroke, diabetes, and even cancer. Maybe now is the best ... that could help them to manage their sleep quality? ... ...
(Date:11/29/2016)... , Nov. 29, 2016   ... identification and object recognition technologies, today released ... for fingerprint recognition solutions that run on ... fingerprint template using less than 128KB of ... compact devices that have limited on-board resources, ...
(Date:11/24/2016)... Cercacor today introduced Ember TM Sport ... non-invasively measure hemoglobin, Oxygen Content, Oxygen Saturation, Perfusion ... in approximately 30 seconds. Smaller than a smartphone, using ... to key data about their bodies to help monitor ... Hemoglobin carries oxygen to muscles. When hemoglobin ...
Breaking Biology News(10 mins):
(Date:12/2/2016)... CytRx Corporation (NASDAQ: CYTR ), ... today announced the appointment of Earl Warren Brien ... private healthcare investor, to its Board of Directors. ... and strategic experience at the highest level," said ... one of the world,s leading orthopedic surgeons, Dr. Brien ...
(Date:12/2/2016)... ... December 01, 2016 , ... ... the value of DNA microarray comparative genomic hybridization (array CGH) for HER2 ... Cancer Symposium. Using molecular test results from tumors with previously documented positive, ...
(Date:12/2/2016)... ... , ... The Conference Forum has announced that the 3rd annual Immuno-Oncology ... February 1-3, 2017 at the Roosevelt Hotel in New York City. Led by advisors ... 360-degree approach, which addresses the most up-to-date information regarding business aspects, clinical advancements and ...
(Date:12/2/2016)... , ... December 02, 2016 ... ... a consortium of pharmaceutical and biotechnology companies dedicated to collaboratively developing improved ... interested in supplying a vendor-supported, portable online UHPLC, with robust, probe-based sampling. ...
Breaking Biology Technology: