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Steroid hormone receptor prefers working alone to shut off immune system genes
Date:12/9/2012

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.


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Contact: Holly Korschun
hkorsch@emory.edu
404-727-3990
Emory University
Source:Eurekalert

Page: 1 2

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