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The Structure of an Important Drug Target Made Crystal Clear

For release: Wednesday, December 5, 2007

Scientists have produced detailed 3-dimensional images of a common type of neurotransmitter receptor, the class of proteins on the receiving end of chemical signals in the nervous system.  The work, funded by the National Institutes of Health (NIH), is expected to speed the development of drugs for a variety of neurological and psychiatric disorders.

In three papers, the researchers published atomic-scale views of the beta2-adrenergic receptor, a protein on the surface of smooth muscle cells.  It's a receptor for adrenalin – the neurochemical behind the body's fight-or-flight response – and a target for drugs used to treat a variety of conditions including asthma and preterm labor.  It's also one of many structurally related proteins known as G-protein-coupled receptors, which include several types of neurotransmitter receptors that are abundant in the brain.

The research was supported by the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of General Medical Sciences (NIGMS), and the NIH Roadmap.  Launched in 2004, the Roadmap's Innovative Membrane Protein Technology initiative supports research to better understand the structure of proteins found in the outer membrane of neurons, muscle cells and other cell types.

"These studies were filled with technical challenges, but the investigators were able to overcome them thanks to the Roadmap's focused investment in membrane protein research," says NINDS Director Story Landis, Ph.D.  "This is only the beginning of the pay-off that the Roadmap will bring to neuroscience."

Structural biologists probe the anatomy of proteins using a technique called X-ray crystallography, which involves crystallizing the proteins and bouncing X-rays off of them.  Most G-protein-coupled receptors are notoriously difficult to crystallize, however, because they are constantly changing shape.  The receptors are active even in the absence of a stimulus like adrenalin.  Their parts are in continuous motion, transmitting information from outside the cell to inside through their tiny, even more mobile partners the G-proteins.

Until now, the only G-protein-coupled receptor to be successfully examined by X-ray crystallography was rhodopsin, the protein that enables cells in the retina to respond to light.  Unlike its shape-shifting relatives, rhodopsin's structure is stable in the absence of its stimulus (light), a feature believed to be important for visual acuity.  As an early step in drug development, researchers have tried using rhodopsin's structure to model the structure of other G-protein-coupled-receptors, but rhodopsin's uniqueness made those attempts problematic.

"An accurate understanding of the structure of G-protein-coupled receptors will facilitate the drug discovery process" says Brian Kobilka, M.D., a molecular physiologist at Stanford University who led the three new studies on the beta2-adrenergic receptor.  Dr. Kobilka is a recipient of the NINDS Javitz award.

Dr. Kobilka and his colleagues at Stanford used two methods to stabilize the beta2-adrenergic receptor and render it easier to crystallize.  In work published in Nature*, they used an antibody to lock onto a flexible piece of the receptor and make it more rigid.  In two studies published in Science**, they used recombinant DNA technology to replace the same flexible piece of the receptor with a small, stable protein. Crystallization experiments on this modified receptor were done in collaboration with Raymond Stevens, Ph.D., and colleagues at Scripps Research Institute in La Jolla.

The studies reveal important differences between the beta2-adrenergic receptor's actual structure and its predicted structure based on rhodopsin.  For one, it has a more open structure than rhodopsin, Dr. Kobilka says.  "The regions that span the membrane aren't bundled as tightly together.  We believe that this contributes to the receptor's basal activity."  This finding is noteworthy, he says, because the receptor's basal activity – not just its adrenalin-dependent activity – could be a target for drug modulation. 

The methods Dr. Kobilka developed could be used to study other G-protein-coupled neurotransmitter receptors that play roles in depression, Parkinson's disease, epilepsy, stroke and other conditions.

*Rasmussen SGF et al.  "Crystal Structure of the Human beta2-Adrenergic G-Protein-Coupled Receptor."  Nature, November 15, 2007, Vol. 450, pp. 383-387.

**Cherezov V et al.  "High-Resolution Crystal Structure of an Engineered Human beta2-Adrenergic G-Protein-Coupled Receptor."  Science, November 23, 2007, Vol. 318, pp. 1258-1265.

**Rosenbaum DM et al.  "GPCR Engineering Yields High-Resolution Structural Insights into beta2-Adrenergic Receptor Function."  Science, Science, November 23, 2007, Vol. 318, pp. 1266-1273.

-By Daniel Stimson, Ph.D.

Last Modified December 5, 2007