Scientists design variant of main painkiller receptor

Scientists have developed a variant of a major painkiller receptor that can be grown in large quantities in bacteria and is also water-soluble, enabling experiments and applications that had previously been very challenging or impossible.
Opioids, such as morphine, are still the most effective class of painkillers, but they come with unwanted side effects and can also be addictive and deadly at high doses.
Designing new pain-killing drugs of this type involves testing them on their corresponding receptors, but access to meaningful quantities of these receptors that can work in experimental conditions has always been a limiting factor.
Now, an interdisciplinary collaboration between researchers at the University of Pennsylvania has developed a variant of the mu opioid receptor that has several advantages when it comes to experimentation.

The mu opioid receptor belongs to a class of cellular membrane proteins called G protein-coupled receptors, or GPCRs.
Involved in wide range of biological processes, these receptors bind to molecules in the environment, initiating cellular signalling pathways.

In the case of this receptor, binding to opioid molecules leads to a profound reduction of pain but also to a variety of unpleasant and potentially fatal side-effects, a problem that researchers from multiple disciplines are attempting to address.
"There are two directions for solving this problem in basic science, either working on the opioid molecule or working on the receptor. We're doing the latter," said lead researcher Renyu Liu.

Experimenting on the mu opioid receptor has been challenging for several reasons. The human receptor itself is relatively scarce, appearing in small quantities on only a few types of cells, making harvesting appreciable amounts impractical.
Researchers have also been unable to grow it recombinantly - genetically engineering bacteria to express the protein en masse - as some parts of the protein are toxic to E coli.
Hydrophobic, or water-hating, amino acid groups on the exterior of the receptor that help it sit in the cell's membrane also make it insoluble in water when isolated.
The researchers set out to address these challenges by computationally designing variants of the mu opioid receptor.

"Based on the comparison of our sequence to the sequences of those GPCRs, we built a computer model of the protein," co-researcher Jeffery Saven said.
From the comparison, the researchers were able to identify the hydrophobic amino acids on the exterior of the structure, as well as some of those that were potentially toxic to E coli.
The research was published in the Journal PLOS ONE.