Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Activation of opioid receptor uncovered

28.11.2019

Together with colleagues from Shanghai, Brussels, Canada and the USA, researchers from the University of Bonn have uncovered the binding mechanism of an important pain receptor. The results facilitate the development of new active substances. The opioids used today to treat severe pain can be addictive and sometimes have life-threatening side effects. The results are published in the renowned journal "Science Advances".

Opioids are among the most effective painkillers available today. They include for instance morphine or oxycodone, which has been prescribed very carelessly in the USA. With serious consequences: Hundreds of thousands of patients have become addicted; many of them later ended up on drugs such as heroin or fentanyl.


Tobias Claff and Prof. Dr. Christa Müller from the University of Bonn are looking at a glass sandwich plate on which the opioid receptor crystals form.

© Photo: Volker Lannert/Uni Bonn


The illustration shows the two new crystal structures of the delta-opioid-(DOP)-receptor in complex with two activating molecules (blue and orange). Morphine, a potent analgesic, is shown in yellow.

© Graphic: Katya Kadyshevskaya/University of Southern California

Oxycodone binds to so-called opioid receptors in the body. There are three different types: MOP, DOP and KOP. The painkillers available to date mainly activate the MOP (also called µ-opioid receptor). However, stimulating MOP can not only be addictive, it can also have life-threatening side effects. The most serious is respiratory paralysis, which is why the most common cause of death after heroin use is respiratory arrest.

"Drugs that selectively bind to the DOP receptor probably do not have these dramatic side effects," hopes Prof. Dr. Christa Müller from the Pharmaceutical Institute at the University of Bonn. The emphasis is on "selective": The opioid receptors are so similar that many drugs activate all three forms. In order to find substances that only dock to the DOP receptor, it is therefore necessary to know exactly what happens during the binding process.

Spatial structure made visible down to the atomic level

The current study can now answer this question. "We have activated the DOP receptor with two different molecules, purified the complex and then elucidated its structure using X-rays," explains Tobias Claff, who carried out the majority of the experiments. For this purpose, the complex of receptor and active substance is transformed into a crystalline state. The crystal lattice deflects the X-ray light in a characteristic manner. The intensity distribution of the diffracted radiation can therefore be used to deduce the spatial structure of the complex, right down to the arrangement of each individual atom.

"This enabled us to show which parts of the receptor are responsible for binding the drugs," says Claff. "This knowledge should now enable the development of targeted new substances that only activate DOP." There is great interest in such drugs, not least because, unlike its MOP counterpart, the DOP receptor is not primarily effective against acute pain, but against chronic pain. This is currently very difficult to treat.

X-ray crystallography is not a new technique. However, the structure of G protein-coupled-receptors (including opioid receptors) could not be resolved until recently. These membrane proteins are located in the thin, fat-like membrane that surrounds the cell contents like a kind of bag. Their fat solubility means that they have to be stabilized at great effort during crystallization. Otherwise they denature and change their spatial structure as a result. "There are only a few laboratories in the world that are capable of dealing with these problems," emphasizes Christa Müller.

At the University of Bonn, aspiring pharmacists can go abroad during their master's or state examination program. The Institute has a broad network of cooperation partners - a fact that is regularly rated very positively in the CHE University Ranking. Tobias Claff used this opportunity: "I spent a year of my master's program at the iHuman institute of the ShanghaiTech University," he explains. “In the last few years, the crystallography of membrane proteins has been crucially advanced there." Claff learned the complex method in Shanghai - a know-how that now also benefits his home university, to which he has meanwhile returned.

Prof. Müller emphasizes that it is not often that a master's student tackles such a complex problem. "This success is an extraordinary achievement," she says. "It also demonstrates the excellent position of the Pharmacy School with its international exchange program."

Wissenschaftliche Ansprechpartner:

Prof. Dr. Christa E. Müller
Pharmaceutical Institute at the University of Bonn
Department of Pharmaceutical and Medicinal Chemistry
Tel. +49 (0)228-732301
E-mail: christa.mueller@uni-bonn.de

Originalpublikation:

Tobias Claff, Jing Yu, Véronique Blais, Nilkanth Patel, Charlotte Martin, Lijie Wu, Gye Won Han, Brian J. Holleran, Olivier Van der Poorten, Michael A. Hanson, Philippe Sarret, Louis Gendron, Vadim Cherezov, Vsevolod Katritch, Steven Ballet, Zhi-Jie Liu, Christa E. Müller, Raymond C. Stevens: Elucidating the active delta-opioid receptor crystal structure with peptide and small molecule agonists. Science Advances, DOI: 10.1126/sciadv.aax9115

Johannes Seiler | idw - Informationsdienst Wissenschaft
Further information:
http://www.uni-bonn.de/

Further reports about: X-ray X-ray light drugs opioid receptor painkillers proteins receptor spatial structure structure

More articles from Health and Medicine:

nachricht Mutations in donors' stem cells may cause problems for cancer patients
17.01.2020 | Washington University School of Medicine

nachricht Overactive brain waves trigger essential tremor
17.01.2020 | Columbia University Irving Medical Center

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Miniature double glazing: Material developed which is heat-insulating and heat-conducting at the same time

Styrofoam or copper - both materials have very different properties with regard to their ability to conduct heat. Scientists at the Max Planck Institute for Polymer Research (MPI-P) in Mainz and the University of Bayreuth have now jointly developed and characterized a novel, extremely thin and transparent material that has different thermal conduction properties depending on the direction. While it can conduct heat extremely well in one direction, it shows good thermal insulation in the other direction.

Thermal insulation and thermal conduction play a crucial role in our everyday lives - from computer processors, where it is important to dissipate heat as...

Im Focus: Fraunhofer IAF establishes an application laboratory for quantum sensors

In order to advance the transfer of research developments from the field of quantum sensor technology into industrial applications, an application laboratory is being established at Fraunhofer IAF. This will enable interested companies and especially regional SMEs and start-ups to evaluate the innovation potential of quantum sensors for their specific requirements. Both the state of Baden-Württemberg and the Fraunhofer-Gesellschaft are supporting the four-year project with one million euros each.

The application laboratory is being set up as part of the Fraunhofer lighthouse project »QMag«, short for quantum magnetometry. In this project, researchers...

Im Focus: How Cells Assemble Their Skeleton

Researchers study the formation of microtubules

Microtubules, filamentous structures within the cell, are required for many important processes, including cell division and intracellular transport. A...

Im Focus: World Premiere in Zurich: Machine keeps human livers alive for one week outside of the body

Researchers from the University Hospital Zurich, ETH Zurich, Wyss Zurich and the University of Zurich have developed a machine that repairs injured human livers and keep them alive outside the body for one week. This breakthrough may increase the number of available organs for transplantation saving many lives of patients with severe liver diseases or cancer.

Until now, livers could be stored safely outside the body for only a few hours. With the novel perfusion technology, livers - and even injured livers - can now...

Im Focus: SuperTIGER on its second prowl -- 130,000 feet above Antarctica

A balloon-borne scientific instrument designed to study the origin of cosmic rays is taking its second turn high above the continent of Antarctica three and a half weeks after its launch.

SuperTIGER (Super Trans-Iron Galactic Element Recorder) is designed to measure the rare, heavy elements in cosmic rays that hold clues about their origins...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

11th Advanced Battery Power Conference, March 24-25, 2020 in Münster/Germany

16.01.2020 | Event News

Laser Colloquium Hydrogen LKH2: fast and reliable fuel cell manufacturing

15.01.2020 | Event News

„Advanced Battery Power“- Conference, Contributions are welcome!

07.01.2020 | Event News

 
Latest News

A new 'cool' blue

17.01.2020 | Life Sciences

EU-project SONAR: Better batteries for electricity from renewable energy sources

17.01.2020 | Power and Electrical Engineering

Neuromuscular organoid: It’s contracting!

17.01.2020 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>