Structural Study Shows Glucocorticoid Receptor Monomers Binding to DNA

Investigators at Emory University (Atlanta, GA, USA) used X-ray crystallography and mechanistic approaches to study the suppressive binding of GR to DNA. They analyzed crystals comprising GR bound to a section of DNA called the thymic stromal lymphopoietin (TSLP) promoter.

Results reported in the December 9, 2012, online edition of the journal Nature Structural & Molecular Biology revealed that GR bound to TSLP 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," said senior author Dr. Eric Ortlund, assistant professor of biochemistry at Emory University.

Analysis of mutations that affect the ability of GR to bind repressive sites showed that binding of the first GR molecule inhibited the binding of a second GR molecule. This "negative cooperativity" may play a role in ensuring that only GR monomers bind to DNA. "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," said Dr. Ortlund.

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