|Structure of opioid receptors mapped|
Two teams of scientists in California have mapped the structure of “kappa” and “mu” opioid receptors in detail for the first time. These receptors play an important role in the function of drugs such as morphine and heroin. This work may help scientists to better understand the mechanism of many drugs and even design safer and more effective medicines such as pain killers.
Opioids are psychoactive chemicals which bind to certain receptors in the body. Medically they can used to treat a variety of conditions such as cough and more commonly pain. Morphine is the prototypical opioid. Opioids also produce a feeling of euphoria which is why they are used recreationally often in the form of the morphine prodrug, heroin. There is a great potential for addiction, which is one of the reasons why their use is carefully controlled and illicit use is considered particularly harmful.
Opioid receptors which these molecules bind to are complex proteins found on the outside of cells in the brain, spinal cord and digestive tract. Teams of scientists have recently mapped the structure of two major types of opioid receptor known as “kappa” and “mu” opioid receptors.
Traditionally the way of understanding the structure of large molecules of this sort is X-ray crystallography. In this method the proteins are packed together into a crystal and rotated as X-rays are passed through the crystal. X-ray images like this were famously used to help uncover the structure of the DNA molecule. Today the X-ray images are combined by computer to recreate the structure of the molecule analytically.
These receptors are extremely complex molecules and so it is difficult to extract them and form them into crystals. Of particular problem are “floppy loops” in the protein which resist tight packing. Scientists have developed a technique of replacing these loops with another stretch of protein allowing the molecules to crystallise. They used special viruses to inject the genetic code into insect cells which then produced vast quantities of the molecules. The molecules were then crystallised and the structure was mapped with X-rays.
The binding pockets in these receptors were found to be large and gaping with many potential sites for molecules to attach to. This may explain why the receptors respond to such as large range of molecules. It could also explain why they are so quickly reversible. For example, the drug naloxone can be used to quickly reverse heroin overdoses, probably because the morphine molecules can easily be freed from the receptors under the influence of the drug. The drug etorphine is a powerful anaesthetic used on the largest animals, such as rhinos, and its effects can be quickly reversed by the drug diprenorphine.
The receptors were found to bind together in tight pairs called dimers lending support to the
hypothesis that the formation of these pairs is an important part of their function. They link together neatly when rotated 180° about the central axis.
The limitation of this imaging technique is that it is impossible observe the dynamic motion of the receptors as they interact with other molecules. When a drug or neurotransmitter known as a ligand binds with the receptor on the surface of the cell, this alters the shape of the receptor which sends signals into the cell to alter its behaviour. These receptors were deliberately disabled by binding to an antagonist. Only the shape of the inactive receptors has been mapped.
Scientist are keen to understand the structure of these molecules as it may help them to design drugs to block or activate specific receptors without having unwanted effects on other similar receptors. This may allow scientists in the future to design a bespoke drug molecule for a particular task rather than having to try many different natural of synthetic chemicals to see if they have any effect. It may be possible to create drugs that only activate receptors in a desired way, such as a powerful painkiller like morphine without the addiction potential.
Article in Nature: http://www.nature.com/news/opioid-receptors-revealed-1.10273
Paper on κ-opiod receptor in Nature: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10939.html
Paper on μ-opioid receptor in Nature: http://www.nature.com/nature/journal/vaop/ncurrent/full/nature10954.html