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Researchers find docking sites for glucocorticoid receptor and Hsp90

University of Oregon researchers have identified protein interactions that regulate the response of cells to steroid hormones. The discovery, they say, could lead to new ways to boost the effectiveness and reduce undesired side effects of steroid-hormone treatments and cancer drugs.

The study, published online this week ahead of regular publication in the Proceedings of the National Academy of Sciences, also uncorks an almost 15-year bottleneck in research caused by difficulties in deciphering the actions of a heat-shock protein known as Hsp90.

Hsp90 belongs to a family of proteins called chaperones that help other proteins achieve and maintain their 3-D structure. Unlike most chaperones, Hsp90 is dedicated to assist a restricted yet diverse group of regulatory proteins, such as the glucocorticoid receptor, which requires help from Hsp90 to interact with hormones. Scientists had been stymied with how Hsp90 recognizes and interacts with client proteins.

Hsp90 activity is becoming a target for drug manufacturers, because cancer cells frequently overproduce this chaperone. Two drugs used commonly to fight cancer, geldanamycin and cisplatin, have been used with success, but researchers only recently learned that the drugs actually act in some as-yet-undetermined way to inhibit Hsp90 interaction with client proteins. __IMAGE_2

Tapping into that knowledge, scientists may be able to develop synthetic molecules that would control specific Hsp90 activity, such as directing the response of cells to glucocorticoids, said the study's principal investigator Beatrice D. Darimont, a professor of chemistry and researcher in the Institute of Molecular Biology at the University of Oregon.

Glucocorticoids are naturally produced by the adrenal glands and are important for a variety of tissue-related activities. They are immune-suppressive and anti-inflammatory, and are prescribed for such conditions as adrenal insufficiency as in Addi
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Source:University of Oregon


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