Navigation Links
First high-res 3D structures of mammalian HSP90 protein solved

Dr. Dan Gewirth, Hauptman-Woodward senior research scientist, has just solved the structure of the first mammalian GRP94 protein implicated in immune diseases such as sepsis, AIDS and certain cancers. His work is being published today in a cover article in a top scientific journal - Molecular Cell.

Gewirths study confirms his 2001 hypothesis that this protein GRP94 is from the same family as the better known HSP90 proteins. As ligand-regulated chaperones proteins that help other cellular proteins achieve their active shapes, the HSP90s are key players in cellular regulation and recognition. The HSP90 proteins have been the subject of increasing international interest as scientists have discovered that they can be targeted therapeutically with drugs that lead to either stimulation as well as inhibition. For example, inhibitors of HSP90s are being developed as therapies for diseases ranging from cancer to sepsis, and drugs that stimulate HSP90 action may be appropriate therapies for diseases involving protein folding, such as cystic fibrosis, prion diseases , and Alzheimers Disease.

Since 2001, Gewirth and his lab have been using the technique of X-ray diffraction to solve the first high-resolution structure of this protein from mammalian origins, to understand its function and to determine if it is indeed a member of the HSP90 family of proteins. The structure and activity patterns of this protein prove conclusively that this is indeed a member of the same family.

Our work opens the door to a more intensive evaluation of this protein both from a mechanistic as well as a therapeutic point of view. In addition to aiding our understanding of the fundamental biology of chaperone-mediated protein folding, this work lays the foundation for the design of drugs that specifically target individual members of the hsp90 family Gewirth, who also holds a post as an associate professor in the Structural Biology department of the University at Buffalo which is housed at the Hauptman-Woodward Medical Research Institute, said.

Why Is This Important?

This is groundbreaking work for a number of reasons: It is the first high resolution picture of any member of the hsp90 family. High resolution is needed for a detailed understanding of protein function. It is also the first structure of a mammalian member of the hsp90 family. This is important since drugs and other therapeutics need to be developed for human use, and thus must target the mammalian protein. Finally, the work shows for the first time how members of the hsp90 family of chaperone proteins can differ from each other, while still being part of the same overall family.

Scientific Understanding

The mammalian member of this protein family is different than those previously studied which were solved from either bacteria or yeast. Human energy production and consumption rates are more similar to those found in the GRP94 proteins than to the more widely studied HSP90 proteins. This means that the insights gained by a greater scientific understanding of how GRP94 works will have more direct applications to human diseases.

Medical Implications and Drug Development

Inhibitors currently are being designed for HSP90 in an attempt to treat the diseases in which HSP90 plays a role. However, these are broad-spectrum inhibitors of all HSP90s which means that unwanted side effects may occur. The Gewirth labs work clarifies GRP94s place in this family and has already stimulated interest in this chaperone as a drug target. This understanding would allow for the long-term development of a family of drugs that could be narrowly targeted for individual proteins, for example specifically treating sepsis only.

Economic Impact

Just as companies have been founded to develop HSP90 inhibitors, the same potential exists here. This will spur a new line of inquiry into GRP94. While this work is its infancy, medicinal chemists will be interested in developing GRP94-targeted drugs, Gewirth said.


Contact: Tara A. Ellis
Hauptman-Woodward Medical Research Institute

Related biology news :

1. A genes first kiss sets off that affair known as puberty
2. Timing is everything: First step in protein building revealed
3. Emory Eye Center Implants Its First Retinal Chips In Patients With Retinitis Pigmentosa
4. First atlas of key brain genes could speed research on cancer, neurological diseases
5. First-ever Compounds To Target Only Metastatic Cells Are Highly Effective Against Breast, Prostate, And Colon Cancers
6. NYCs First Rapid HIV Drug-resistant AIDS Case Prompts Call to Step Up HIV Prevention
7. First real-time view of developing neurons reveals surprises, say Stanford researchers
8. Love at first smell
9. Worlds largest rainforest drying experiment completes first phase
10. PCRM develops worlds first cruelty-free insulin assay
11. Breast-Cancer Risk Linked to Exposure to Traffic Emissions at Menarche, First Birth
Post Your Comments:
(Date:11/16/2015)... SAN JOSE, Calif. , Nov 16, 2015 ... leading developer of human interface solutions, today announced ... new Synaptics TouchView ™ touch controller and ... the architectural revolution of smartphones. These new TDDI ... and include TD4100 (HD resolution), TD4302 (WQHD resolution), ...
(Date:11/11/2015)... , Nov. 11, 2015   MedNet Solutions , an ... of clinical research, is pleased to announce that it will ... Trials (PCT) event, to be held November 17-19 in ... to view live demonstrations of iMedNet , ... how iMedNet has been able to deliver time ...
(Date:11/9/2015)... Calif. , Nov. 9, 2015  Synaptics Inc. ... interface solutions, today announced broader entry into the automotive ... solutions that match the pace of consumer electronics human ... biometric sensors are ideal for the automotive industry and ... Europe , ...
Breaking Biology News(10 mins):
(Date:11/27/2015)... ... November 27, 2015 , ... ... that includes over 2,000 technical presentations offered in symposia, oral sessions, workshops, awards, ... spectroscopy, covers a wide range of applications such as, but not limited to, ...
(Date:11/26/2015)... , November 26, 2015 /PRNewswire/ ... --> Accutest Research Laboratories, ... Contract Research Organization (CRO), has formed ... Cancer Center - Temple Health for ... ,     (Photo: ) , ...
(Date:11/25/2015)... November 26, 2015 ... Market 2016 - 2020 report analyzes that automating ... and quality in long-term samples, minimizing manual errors, ... Automation minimizes manual errors such as mislabeling or ... Further, it plays a vital role in blood ...
(Date:11/25/2015)... 2 nouvelles études permettent d , identifier ... souches bactériennes retrouvées dans la plaque dentaire des ... Ces recherches  ouvrent une nouvelle voie ... l,un des problèmes de santé les plus fréquemm ... --> 2 nouvelles études permettent d , ...
Breaking Biology Technology: