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 New type of photosynthesis discovered
17.06.2018 | Imperial College London

nachricht New ID pictures of conducting polymers discover a surprise ABBA fan
17.06.2018 | University of Warwick

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: AchemAsia 2019 will take place in Shanghai

Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.

Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...

Im Focus: First real-time test of Li-Fi utilization for the industrial Internet of Things

The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.

Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.

Im Focus: Sharp images with flexible fibers

An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.

Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...

Im Focus: Photoexcited graphene puzzle solved

A boost for graphene-based light detectors

Light detection and control lies at the heart of many modern device applications, such as smartphone cameras. Using graphene as a light-sensitive material for...

Im Focus: Water is not the same as water

Water molecules exist in two different forms with almost identical physical properties. For the first time, researchers have succeeded in separating the two forms to show that they can exhibit different chemical reactivities. These results were reported by researchers from the University of Basel and their colleagues in Hamburg in the scientific journal Nature Communications.

From a chemical perspective, water is a molecule in which a single oxygen atom is linked to two hydrogen atoms. It is less well known that water exists in two...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Munich conference on asteroid detection, tracking and defense

13.06.2018 | Event News

2nd International Baltic Earth Conference in Denmark: “The Baltic Sea region in Transition”

08.06.2018 | Event News

ISEKI_Food 2018: Conference with Holistic View of Food Production

05.06.2018 | Event News

 
Latest News

A sprinkle of platinum nanoparticles onto graphene makes brain probes more sensitive

15.06.2018 | Materials Sciences

100 % Organic Farming in Bhutan – a Realistic Target?

15.06.2018 | Ecology, The Environment and Conservation

Perovskite-silicon solar cell research collaboration hits 25.2% efficiency

15.06.2018 | Power and Electrical Engineering

VideoLinks
Science & Research
Overview of more VideoLinks >>>