05.17.12

Bright Lights, Big Molecules and Hopefully a Better Understanding of Addictions

Researchers supported by Argonne Lab's Advanced Photon Source determine the structure of two opioid receptors.

Click to enlarge photo.Enlarge Photo

Structure of the human kappa opioid receptor in complex with JDTic Protein Data Bank

Structure of the human kappa opioid receptor in complex with JDTic

Addictions can be complicated. That's as true for the cheerful buzz of an essential workout as it is for a far more dangerous syndrome.

But understanding them may have become a bit simpler, thanks to scientists using the Advanced Photon Source (APS) at Argonne National Lab. The APS creates extremely bright storage ring-generated X-ray beams, so bright that researchers can use them to reveal the positions of individual atoms in large and complex molecules.

Two teams of scientists recently used the APS to reveal the structure of two molecules that have a lot to do with addiction, opioid receptors. Opioids include prescription pain-relievers like morphine and oxycodone, as well as horribly harmful heartbreakers like heroin. They've different names, but opioids all work in roughly the same way, by binding to opioid receptors in the brain, in similar fashion to how a key goes into a lock.

Opioid receptors themselves belong to a special class of cellular signalers called G-protein-coupled-receptors (GPCRs). GPCRs are vital cellular communications devices: They pick up incoming signals from outside, and then tell the cell what to do about them through chemical cascades. That makes them the target of many medicines.

However, it's also extremely difficult to determine the exact structure of GPCRs. Before a protein structure can be determined by x-ray diffraction, it has to be crystallized, and that's where GPCRs make it tough. They're large proteins with greasy, lipid insides and loose, liquid-like extensions on the outside, both of which make them extremely difficult to be crystallized.

In fact, it took Dr. Brian Kobilka and his team at Stanford University almost two decades of tries before they finally succeeded in crystallizing a GPCR. They then used the macromolecular crystallography capabilities of the National Institutes of Health's (NIH), National Institute of General Medical Sciences (GM) and the National Cancer Institute (CA) beamlines (GM/CA) at Argonne Lab's APS to determine the structure of the protein, in findings announced last fall. (For more information see A Cellular Cell.)

Dr. Kobilka led one team in using the APS to determine the structure of the µ (mu) opioid receptor, while another team led by Raymond Stevens of the Scripps Research institute determined the structure of the κ (kappa) opioid receptor. The two groups have also published details of a few other GPCRs this year, and the structures of several others are on the way.

Kobilka's team received support from Stanford University, the National Science Foundation, and the National Institutes of Health, among other sources. Stevens's team was supported by the National Institutes of Health; some x-ray characterization was also performed by the Naval Research Laboratory. The APS is supported by the DOE Office of Science.

In determining the atomic structure of the opioid receptors, the teams found a couple of distinct traits. For instance, their binding sites, where the opioid "key" fits into the receptor "lock", are relatively large and deep. That might help explain why there's such a variety of opioids (the large size of the lock allows many different keys to work), as well as why people experience their effects so quickly.

These insights into opioid receptors may eventually suggest new drug targets, and perhaps even new medical treatments. And the rapidly growing knowledge of the structures of G-protein-coupled-receptors that researchers are gaining via x-ray light sources supported by Office of Science could lead to incredible new possibilities. That might not make dealing with addictions any easier, but it could make understanding them a bit simpler, and hopefully make a lot of lives a lot healthier.

The Department's Office of Science is the single largest supporter of basic research in the physical sciences in the United States, and is working to address some of the most pressing challenges of our time. For more information about Argonne National Laboratory, please go to: http://www.anl.gov/External link.

Charles Rousseaux is a Senior Writer in the Office of Science.

Last modified: 7/15/2013 12:10:41 PM