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 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.
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.
Journal Reference:
- William H Hudson, Christine Youn, Eric A Ortlund. The structural basis of direct glucocorticoid-mediated transrepression. Nature Structural & Molecular Biology, 2012; DOI: 10.1038/nsmb.2456
Courtesy: ScienceDaily
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