Molecular mechanism addictive substances

Molecular mechanism of addictive substances

4:34 AM, 26th April 2012
Molecular mechanism of addictive substances
Crystal structure of the mu-opioid receptor bound to a morphinan antagonist.

ILLINOIS, US: Researchers and doctors have gleaned new clues to the molecular mechanisms behind some of the most addictive substances in the world. The new studies have uncovered the structures of some of the most intricate and challenging proteins ever analyzed on the atomic level. The US Department of Energy’s (DOE) Argonne National Laboratory determined the composition of brain receptors that bind to opioids, the class of molecules that includes morphine, heroin and oxycodone.

The experiments show that the binding sites of both µ (mu) and k (kappa) opioid receptors are relatively large and open, which researchers believe could help explain both why they recognize an array of molecules and why opioids are processed so quickly by the brain. Opioid receptors belong to a class of molecules known as G-protein coupled receptors (GPCRs), which are typically proteins that sense other molecules that exist in the area immediately outside the cell membrane. For decades, the exact configurations of GPCRs have flummoxed scientists.

“The GPCRs are such a diverse family in terms of their function, but until very recently we just didn’t have the technology required to learn about their structures,” said Robert Fischetti, Senior Scientist, Argonne. When a GPCR senses its target molecule, it triggers a series of changes within the cell. GPCRs help to fulfill a number of different biological roles, including enabling vision and the sense of smell, and, in the case of receptors for opioids and other brain chemicals, regulating behaviour and mood.

According to Insight Pharma Reports, roughly 30 to 40 per cent of all current drug development is targeted for GPCRs. Fischetti and Janet Smith, University of Michigan manage a suite of National Institutes of Health-supported beamlines where researchers use high-energy X-rays to probe the molecular structures of many different proteins. These beamlines, named for the National Institute of General Medicine Sciences and National Cancer Institute Collaborative Access Team (GM/CA-CAT), allow visiting protein crystallographers to work around the clock to study proteins involved in biological pathways that regulate both normal functioning and disease. These beamlines specializes in intense, tunable micro-beams for crystallography.

According to Ruslan Sanishvili, Crystallographer, Argonne, one principal feature of GM/CA-CAT that makes it especially attractive for protein crystallography is the development of a device known as a quad collimator, which allows researchers to shrink the size of the X-ray beam with a click of a button. This ‘minibeam’ device together with a special ‘rastering’ software programme enables the analysis of significantly smaller or otherwise inferior crystals than ever before.

“GPCRs are known for being relatively difficult to crystallize, this was one of the main reasons the biological community had been having such a hard time understanding their structures. The minibeam and rastering software were key tools that opened the door to this new class of protein structures,” said Michael Becker, Crystallographer, Argonne.

© Argonne National Laboratory News



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