Navigation Links
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 son's disease, arthritis, asthma, inflammatory bowel disease and childhood acute lymphoblastic leukemia.

"Glucocorticoids are very commonly used in the treatment of diseases," Darimont said. "They have a bunch of physiological activities and functions, and responses are very different depending on the cells involved. The treatments are extremely effective, and glucocorticoids have been used in huge amounts in the last 40 years. Unfortunately, they are associated with very severe side effects. "

Side effects include osteoporosis, cataracts, ulcers, hypertension, impaired wound healing, diabetes and depression. Thus narrowing the point of attack, such as by manipulating Hsp90-glucocorticoid receptor interaction, is of growing importance, Darimont said.

The PNAS paper and a second publication that is under review cover the identification of the features of the glucocorticoid receptor (GR) recognized by Hsp90 and two sites on Hsp90 that interact with GR. To identify these sites, Darimont's team investigated 49,000 randomly introduced GR mutants and 11 specifically designed Hsp90 mutants for their binding and activation abilities. Finding and confirming the two binding sites were boosted by the recently published crystallized structures of both Hsp90 and GR, Darimont said.

"Our results suggest that Hsp90 binds GR with the help of specific docking sites in the C-terminal domain of Hsp90," she said. "This finding opens the possibility to develop small molecules that block specific Hsp90-client protein interactions. As part of our work, we also have identified GR mutants that are able to bind hormones without Hsp90, which may facilitate the development of novel synthetic glucocorticoids."
'"/>

Source:University of Oregon


Related biology news :

1. Researchers discover way to make cells in the eye sensitive to light
2. Researchers find how protein allows insects to detect and respond to pheromones
3. Researchers Uncover Key Step In Manufacture of Memory Protein
4. Researchers reveal the infectious impact of salmon farms on wild salmon
5. Researchers identify target for cancer drugs
6. Researchers discover molecule that causes secondary stroke
7. Researchers find missing genes of ancient organism
8. Researchers trace evolution to relatively simple genetic changes
9. Researchers add new tool to tumor-treatment arsenal
10. UF Researchers Map Bacterial Proteins That Cause Tooth Loss
11. VCU Researchers Identify Networks Of Genes Responding To Alcohol In The Brain

Post Your Comments:
*Name:
*Comment:
*Email:


(Date:4/28/2016)... and BANGALORE, India , April 28, 2016 ... a product subsidiary of Infosys (NYSE: INFY ), ... a global partnership that will provide end customers ... mobile banking and payment services.      (Logo: ... innovation area for financial services, but it also plays a ...
(Date:4/26/2016)... DUBLIN , April 27, 2016 ... of the  "Global Multi-modal Biometrics Market 2016-2020"  report ... ) , The analysts forecast ... a CAGR of 15.49% during the period 2016-2020.  ... a number of sectors such as the healthcare, ...
(Date:4/15/2016)... DUBLIN , April 15, 2016 ... of the,  "Global Gait Biometrics Market 2016-2020,"  report ... http://photos.prnewswire.com/prnh/20160330/349511LOGO ) , ,The global gait ... CAGR of 13.98% during the period 2016-2020. ... movement angles, which can be used to compute ...
Breaking Biology News(10 mins):
(Date:6/23/2016)... /PRNewswire/ - FACIT has announced the creation of ... company, Propellon Therapeutics Inc. ("Propellon" or "the Company"), ... portfolio of first-in-class WDR5 inhibitors for the treatment ... represent an exciting class of therapies, possessing the ... cancer patients. Substantial advances have been achieved with ...
(Date:6/23/2016)... , June, 23, 2016  The Biodesign Challenge ... envision new ways to harness living systems and biotechnology, ... Art (MoMA) in New York City ... 130 participating students, showcased projects at MoMA,s Celeste Bartos ... Paola Antonelli , MoMA,s senior curator of architecture and ...
(Date:6/23/2016)... , June 23, 2016 Apellis ... Phase 1 clinical trials of its complement C3 ... single and multiple ascending dose studies designed to ... (PD) of subcutaneous injection in healthy adult volunteers. ... (SC) either as a single dose (ranging from ...
(Date:6/23/2016)... ... June 23, 2016 , ... Regulatory ... technical consulting, provides a free webinar on Performing Quality Investigations: Getting ... at 12pm CT at no charge. , Incomplete investigations are still a major ...
Breaking Biology Technology: