Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Steroid hormone receptor prefers working alone to shut off immune system genes

10.12.2012
Researchers at Emory University School of Medicine have obtained a detailed molecular picture that shows how glucocorticoid hormones shut off key immune system genes.

The finding could help guide drug discovery efforts aimed at finding new anti-inflammatory drugs with fewer side effects.

The results are scheduled for publication Sunday, Dec. 9 by the journal Nature Structural & Molecular Biology.

Synthetic glucocorticoid hormones – for example, prednisone and dexamethasone -- are widely used to treat conditions such as allergies, asthma, autoimmune diseases and cancer. They mimic the action of the natural hormone cortisol, which is involved in the response to stress and in regulating metabolism and the immune system. For this reason, synthetic glucocorticoids have a variety of severe side effects such as increased blood sugar and reduced bone density.

Both cortisol and synthetic hormones act by binding the glucocorticoid receptor, a protein that binds DNA and turns some genes on and others off. The hormone is required for the glucocorticoid receptor (GR) to enter the nucleus, giving it access to DNA.

For GR-targeting therapeutics, the desired anti-inflammatory effects are thought to come mainly from turning off inflammatory and immune system genes, while the side effects result from turning on genes involved in processes such as metabolism and bone growth.

The mechanism driving GR anti-inflammatory action has been debated, since was no GR binding site identified near these anti-inflammatory genes. Thus, GRs immunosupression was thought to occur indirectly, whereby GR blocks the ability of other critical DNA-binding proteins to stimulate gene expression. Last year French scientists discovered that the GR turns some immune system genes off directly by recognizing a distinct DNA sequence used only in gene repression. http://www.ncbi.nlm.nih.gov/pubmed/21496643

Eric Ortlund, PhD, Emory assistant professor of biochemistry, and first author William Hudson, a Molecular and Systems Pharmacology graduate student, used X-rays to probe crystals of GR bound to a stretch of DNA where it acts "repressively" to shut down the transcription of immune genes.

When the GR turns genes on, two GR molecules grasp each other while binding to DNA. However, the mode of binding to DNA at repressive sequences had remained unknown. Their analysis demonstrated that GR binds to repressive sites in pairs, but with two monomeric GR molecules located on opposite sides of the DNA helix.

"This unexpected geometry was still a surprise because GR has never been crystallized as a monomer bound to DNA, though previous studies proposed that GR monomers repress genes as opposed to GR dimers, which activate genes," says Ortlund.

In addition, the two GR molecules bind to different DNA sequences within the repressive DNA element, Hudson and Ortlund found. They also analyzed how mutations affected the ability of GR to bind repressive sites, showing that binding of the first GR molecule inhibits the binding of a second GR molecule. This "negative cooperativity" may play a role in ensuring that only GR monomers bind to DNA.

The study suggests that a drug preventing GR from interacting with other GR molecules while still allowing them to bind DNA and turn genes off may have anti-inflammatory effects with fewer side effects. One such plant-based compound, "compound A," has been under investigation by several laboratories.

"Our structural data could help scientists design synthetic hormones that separate these two aspects of GR function, potentially leading to improved steroid hormones for diseases ranging from asthma to autoimmune disorders," says Ortlund.

Grants: startup funds, National Institute of General Medical Sciences 5T32GM008602.

W.H. Hudson, C. Youn and E.A. Ortlund. The structural basis of direct glucocorticoid-mediated transrepression. Nat. Struct. Mol. Biol (2012).

Writer: Quinn Eastman

Holly Korschun | EurekAlert!
Further information:
http://www.emory.edu

More articles from Life Sciences:

nachricht Bolstering fat cells offers potential new leukemia treatment
17.10.2017 | McMaster University

nachricht Ocean atmosphere rife with microbes
17.10.2017 | King Abdullah University of Science & Technology (KAUST)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Ocean atmosphere rife with microbes

17.10.2017 | Life Sciences

Neutrons observe vitamin B6-dependent enzyme activity useful for drug development

17.10.2017 | Life Sciences

NASA finds newly formed tropical storm lan over open waters

17.10.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>