Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Every atom counts

05.08.2016

Malignant cancer cells not only proliferate faster than most body cells. They are also more dependent on the most important cellular garbage disposal unit, the proteasome, which degrades defective proteins. Therapies for some types of cancer exploit this dependence: Patients are treated with inhibitors, which block the proteasome. The ensuing pile-up of junk overwhelms the cancer cell, ultimately killing it. Scientists have now succeeded in determining the human proteasome’s 3D structure in unprecedented detail and have deciphered the mechanism by which inhibitors block the proteasome. Their results will pave the way to develop more effective proteasome inhibitors for cancer therapy.

In order to understand how cellular machines such as the proteasome work, it is essential to determine their three-dimensional structure in detail. With its more than 50000 atoms, the barrel-shaped proteasome, however, is a true challenge for structural biologists.


Tailored parallel X-rays perfectly matching the dimensions of the protein crystals enabled the scientists to determine the proteasome structure in unprecedented detail.

Hartmut Sebesse / Max Planck Institute for Biophysical Chemistry

A group of scientists led by Ashwin Chari at the Max Planck Institute (MPI) for Biophysical Chemistry in Göttingen and Gleb Bourenkov at EMBL have now managed to determine the three-dimensional structure of the human proteasome at an unprecedented resolution of 1.8 Ångström – enabling them to pinpoint the position of single atoms in the garbage disposal unit.

In a next step, the researchers solved the structure of the proteasome bound to four different inhibitors that are either already used in the clinic or are currently undergoing clinical trials. “The substantial improvement in resolution compared to previous proteasome structures has allowed us to establish the exact chemical mechanism by which inhibitors block the proteasome.

This knowledge makes it possible to optimize inhibitor design and efficacy – since only inhibitors tailored to the proteasome shut it down completely,” says Chari, project group leader in the Department of Structural Dynamics headed by Holger Stark at the MPI for Biophysical Chemistry.

The scientists discovered an important detail in the proteasome’s active site. The active site is what enables the proteasome to degrade the cell’s junk, and it is what the inhibitor drugs bind to in order to shut off that activity. In contrast to the common perception, a 7-ring structure is formed by the chemical reaction of inhibitor and proteasome active site, which contains an additional so-called methylene group.

This has far-reaching consequences for the inhibitor’s efficacy and chemical mechanism, the researchers explain. “Even though a methylene group just comprises one carbon atom and its two associated protons amidst the more than 50000 atoms of the proteasome, it decisively influences which chemical features make the inhibitor most effective in blocking the proteasome,” says Thomas Schneider, who leads a group at EMBL.

“This has to be taken into account when developing new inhibitors and searching for new drug candidates,” adds Holger Stark. The researchers have already filed a patent application for the chemical procedure to design such inhibitors. “Clinical applications are always preceded by knowledge about targets – therefore, the details, where every atom counts, make all the difference,” Bourenkov states.

Huge effort reveals a small difference

The project’s success is the result of fantastic teamwork, as Max Planck researcher Chari emphasizes: “A group of scientists, all experts in their respective fields, contributed their specialized knowledge, expertise, and complemented each other perfectly.” Structural biologists, physicists, enzymologists, and biochemists of the MPI for Biophysical Chemistry, EMBL, and the University of Göttingen developed several innovative procedures.

To determine a molecule’s structure using X-ray crystallography, scientists grow crystals of that molecule, then shine a powerful beam of X-ray light on the crystal. Based on how the X-rays scatter after hitting the crystal, researchers can deduce the molecule’s 3D structure. Fabian Henneberg and Jil Schrader, junior scientists in Stark’s department and first authors of the report now published in Science, used a new method to purify proteasomes and grow the high-quality crystals that made it possible to solve its 3D structure in such detail.

The scientists have filed for a second patent application based on the purification and crystallization procedure employed in this work. “The pipeline we use to purify and crystallize the proteasome with and without inhibitors is also suitable to discover new proteasome inhibitors – in an industrial setting, screening several hundred compounds per week could be feasible,” Chari predicts.

However, the crystals were only one element of the project’s success. The second were the cutting-edge instruments developed by the EMBL research facility on the Deutsches Elektronen Synchrotron (DESY) campus in Hamburg. “The DESY light source generates X-rays of exceptional quality. With the help of powerful X-ray optics, we were able to tailor X-rays to perfectly suit the crystallized proteasome. Only this made it possible to determine the proteasome structure in unprecedented detail,” concludes Bourenkov.

The X-ray optics used in this work were installed in DESY’s PETRA III hall in 2015 thanks to funding from the German Federal Ministry for Education and Research´s (BMBF) RÅC support scheme.

Original publication
Schrader J, Henneberg F, Mata R, Tittmann K, Schneider TR, Stark H, Bourenkov G, Chari A: The inhibition mechanism of human 20S proteasomes enables next-generation inhibitor design. Science, August 5, 2016, doi:10.1126/science.aaf8993

Contact
Dr. Ashwin Chari, Department of Structural Dynamics,
Max Planck Institute for Biophysical Chemistry, Göttingen
Phone: +49 551 201-1654
E-mail: ashwin.chari@mpibpc.mpg.de

Dr. Gleb Bourenkov
EMBL Hamburg
Phone: +49 40 89902-120
E-mail: gleb@embl-hamburg.de

Dr. Carmen Rotte, Press and Public Relations
Max Planck Institute for Biophysical Chemistry, Göttingen
Phone: +49 551 201-1304
E-mail: carmen.rotte@mpibpc.mpg.de

Sonia Furtado Neves, Press Office
EMBL
Phone: +49 6221 387 8263
E-mail: sonia.furtado@embl.de, pressoffice@embl.de

Weitere Informationen:

http://www.mpibpc.mpg.de/15429219/pr_1628 - Original press release
http://www.mpibpc.mpg.de/stark – Webpage of the Department of Structural Dynamics, Max Planck Institute for Biophysical Chemistry, Göttingen
http://www.embl-hamburg.de/research/unit/schneider – Webpage of the Schneider group, EMBL, Hamburg

Dr. Carmen Rotte | Max-Planck-Institut für biophysikalische Chemie

More articles from Life Sciences:

nachricht Discovery of genes involved in the biosynthesis of antidepressant
09.12.2019 | Leibniz Institute of Plant Genetics and Crop Plant Research

nachricht Scientists have spotted new compounds with herbicidal potential from sea fungus
09.12.2019 | Far Eastern Federal University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Electronic map reveals 'rules of the road' in superconductor

Band structure map exposes iron selenide's enigmatic electronic signature

Using a clever technique that causes unruly crystals of iron selenide to snap into alignment, Rice University physicists have drawn a detailed map that reveals...

Im Focus: Developing a digital twin

University of Texas and MIT researchers create virtual UAVs that can predict vehicle health, enable autonomous decision-making

In the not too distant future, we can expect to see our skies filled with unmanned aerial vehicles (UAVs) delivering packages, maybe even people, from location...

Im Focus: The coldest reaction

With ultracold chemistry, researchers get a first look at exactly what happens during a chemical reaction

The coldest chemical reaction in the known universe took place in what appears to be a chaotic mess of lasers. The appearance deceives: Deep within that...

Im Focus: How do scars form? Fascia function as a repository of mobile scar tissue

Abnormal scarring is a serious threat resulting in non-healing chronic wounds or fibrosis. Scars form when fibroblasts, a type of cell of connective tissue, reach wounded skin and deposit plugs of extracellular matrix. Until today, the question about the exact anatomical origin of these fibroblasts has not been answered. In order to find potential ways of influencing the scarring process, the team of Dr. Yuval Rinkevich, Group Leader for Regenerative Biology at the Institute of Lung Biology and Disease at Helmholtz Zentrum München, aimed to finally find an answer. As it was already known that all scars derive from a fibroblast lineage expressing the Engrailed-1 gene - a lineage not only present in skin, but also in fascia - the researchers intentionally tried to understand whether or not fascia might be the origin of fibroblasts.

Fibroblasts kit - ready to heal wounds

Im Focus: McMaster researcher warns plastic pollution in Great Lakes growing concern to ecosystem

Research from a leading international expert on the health of the Great Lakes suggests that the growing intensity and scale of pollution from plastics poses serious risks to human health and will continue to have profound consequences on the ecosystem.

In an article published this month in the Journal of Waste Resources and Recycling, Gail Krantzberg, a professor in the Booth School of Engineering Practice...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

The Future of Work

03.12.2019 | Event News

First International Conference on Agrophotovoltaics in August 2020

15.11.2019 | Event News

Laser Symposium on Electromobility in Aachen: trends for the mobility revolution

15.11.2019 | Event News

 
Latest News

The Arctic atmosphere - a gathering place for dust?

09.12.2019 | Earth Sciences

New ultra-miniaturized scope less invasive, produces higher quality images

09.12.2019 | Information Technology

Discovery of genes involved in the biosynthesis of antidepressant

09.12.2019 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>