Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers find docking sites for glucocorticoid receptor and Hsp90

21.11.2006
Heat shock proteins prove to be vital, will be prime targets for drug design

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.

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 Addison'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."

Jim Barlow | EurekAlert!
Further information:
http://www.uoregon.edu

Further reports about: Darimont Glucocorticoid Hsp90 Interaction Protein chaperone receptor

More articles from Life Sciences:

nachricht Rainbow colors reveal cell history: Uncovering β-cell heterogeneity
22.09.2017 | DFG-Forschungszentrum für Regenerative Therapien TU Dresden

nachricht The pyrenoid is a carbon-fixing liquid droplet
22.09.2017 | Max-Planck-Institut für Biochemie

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

Im Focus: Ultrafast snapshots of relaxing electrons in solids

Using ultrafast flashes of laser and x-ray radiation, scientists at the Max Planck Institute of Quantum Optics (Garching, Germany) took snapshots of the briefest electron motion inside a solid material to date. The electron motion lasted only 750 billionths of the billionth of a second before it fainted, setting a new record of human capability to capture ultrafast processes inside solids!

When x-rays shine onto solid materials or large molecules, an electron is pushed away from its original place near the nucleus of the atom, leaving a hole...

Im Focus: Quantum Sensors Decipher Magnetic Ordering in a New Semiconducting Material

For the first time, physicists have successfully imaged spiral magnetic ordering in a multiferroic material. These materials are considered highly promising candidates for future data storage media. The researchers were able to prove their findings using unique quantum sensors that were developed at Basel University and that can analyze electromagnetic fields on the nanometer scale. The results – obtained by scientists from the University of Basel’s Department of Physics, the Swiss Nanoscience Institute, the University of Montpellier and several laboratories from University Paris-Saclay – were recently published in the journal Nature.

Multiferroics are materials that simultaneously react to electric and magnetic fields. These two properties are rarely found together, and their combined...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Rainbow colors reveal cell history: Uncovering β-cell heterogeneity

22.09.2017 | Life Sciences

Penn first in world to treat patient with new radiation technology

22.09.2017 | Medical Engineering

Calculating quietness

22.09.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>