27. November 2019

Activation of opioid receptors elucidated Activation of opioid receptors elucidated

PhD student Tobias Claff from the working group of PZB spokesperson Prof. Dr. Christa E. Müller, in collaboration with research colleagues from Shanghai, Brussels Canada and the USA, was able to use X-ray crystallography to show which parts of the receptor are responsible for binding the active substances. With this knowledge, it should be possible to develop substances that activate only DOP.

Structure opioid receptor elucidated
Structure opioid receptor elucidated - f.l.t.r.: Tobias Claff, Prof. Christa E.Müller © Uni Bonn
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Researchers at the University of Bonn, together with colleagues from Shanghai, Brussels, Canada and the USA, have elucidated 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 some have life-threatening side effects. The results appear in the renowned journal "Science Advances".

Opioids are among the most effective painkillers available today. They include, for example, morphine and oxycodone, which was often prescribed very lightly in the U.S. in the past. With serious consequences: Hundreds of thousands of patients became addicted; many of them later ended up with drugs such as heroin or fentanyl.

Oxycodone binds in the body to so-called opioid receptors. There are three different types of these - MOP, DOP and KOP. The painkillers available to date mainly activate the M form (also called µ receptor). However, stimulation of MOP can not only be addictive, but can additionally have life-threatening side effects. Probably the most serious is paralysis of the respiratory center. The most common cause of death after heroin use, then, is respiratory failure.

"Drugs that bind selectively to the DOP receptor are unlikely to have these drastic side effects," hopes Prof. Dr. Christa Müller of the Pharmaceutical Institute at the University of Bonn. The emphasis is on "selective":The opioid receptors are so similar that many active substances activate all three forms. In order to find substances that specifically dock only to the DOP receptor, it is therefore necessary to know exactly what happens during binding.

Spatial structure made visible down to the atomic level

The current study can now answer this question. "We activated the DOP receptor with two different molecules, purified the complex and then elucidated its structure with X-rays," explains Tobias Claff, who performed the main part of the experiments. To do this, the complex of receptor and active ingredient is converted into a crystalline state. The crystal lattice deflects the X-ray light in a characteristic way. The intensity distribution of the diffracted radiation can therefore be used to infer the spatial structure of the complex - right down to the arrangement of each individual atom.

"We were thus able to show which parts of the receptor are responsible for binding the active substances," says Claff. "With this knowledge, it should now be possible to produce very targeted new substances that exclusively activate DOP." There is great interest in such pharmaceuticals - not least because the DOP receptor, unlike its MOP counterpart, is not primarily effective against acute pain, but against chronic pain. Until now, these have been very difficult to treat.

X-ray crystallography is not a new technique. However, the structure of so-called G-protein-coupled receptors (including the opioid receptors) could not be elucidated in this way until recently. These membrane proteins are located in the thin fat-like membrane that encloses the cell contents like a kind of pouch. Due to their fat-solubility, they must be stabilized during crystallization. Otherwise, they denature and thus change their spatial structure. "There are only a few laboratories worldwide that have mastered these problems," Christa Müller emphasizes.

At the University of Bonn, prospective pharmacists can go abroad during their master's or state examination. The institute has a broad network of cooperation partners for this purpose - a fact that is also regularly rated very positively in the CHE study rankings, for example. Tobias Claff took advantage of this opportunity: "I spent a year of my master's degree at an institute at ShanghaiTech University," he explains. "There, the crystallography of membrane proteins has been decisively advanced in recent years." In Shanghai, Claff learned the elaborate method - a know-how that now also benefits his home university, to which he has since returned.

It is not often that a master's student tackles such a difficult problem, emphasizes Prof. Müller. "This success is quite an extraordinary achievement," she says. "It also shows how well the Pharmacy Division is positioned with its international exchange program."

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