Scientists from The Scripps Research Institute have determined the structure of an adenosine receptor that plays a critical role in a number of important physiological processes including pain, breathing, and heart function. The findings could lead to the development of a new class of therapeutics for treating numerous neurological disorders, including Parkinson's and Huntington disease. The study was published on October 2, 2008, in Science Express.

"We are developing a robust platform for studying human G protein-coupled receptor structure and function," Raymond Stevens, a Scripps Research scientist and professor. "This work lays a strong foundation for understanding drug-receptor interactions. We expect to continue our work and develop a deep understanding as to how drugs interact with the broader class. The findings—and our future research—could one day lead to the development of a novel class of therapeutics with improved pharmaceutical properties."

The study defined the structure of the human A2A adenosine receptor—sometimes referred to as the "caffeine receptor"—which falls in the larger family of G protein-coupled receptors (GPCR).

"Last year, we determined the structure of the β2-adrenergic G protein-coupled receptor with multiple ligands," said Stevens . "The big question then was—is it going to be another 10 years until we get the next new receptor? The answer is 'no.' It has taken less than a year to determine this new structure. Our expectation is that even more will come out in the next few years."  Because of the importance of GPCRs to health and medicine and previous lack of knowledge about their structure, the Stevens lab's 2007 research solved the structure of the β2-adrenergic G protein-coupled receptor and was selected as one of the top 10 breakthroughs of the year by Science magazine.

In the new study, the Stevens laboratory worked with the IJzerman laboratory at the Leiden/Amsterdam Center for Drug Research in The Netherlands, to illuminate the A2A adenosine receptor. This receptor is blocked by methylxanthines like caffeine, which prevents the binding of other naturally occurring ligands. Interestingly, there is evidence that coffee drinkers have a lower risk of Parkinson's disease.

Because membrane proteins like adenosine receptors have been notoriously difficult to crystallize—a key step in determining the structure of a molecule through the technique of x-ray crystallography—the scientists bound the A2A adenosine receptor to a high-affinity antagonist, ZM241385. ZM241385, which had been developed as a potential drug to combat Parkinson's disease, stabilizes the receptor.

With the two molecules bound together, the scientists were able to obtain crystals of the complex, and determine its structure. The crystallographic model of the A2A receptor bound to ZM241385 reveals features distinct from previously reported GPCR structures.

In the new study, the A2A adenosine-ligand bound structure suggests that there is no general receptor binding pocket conserved across the adenosine receptor family. Rather, the pocket itself can vary in position and orientation, yielding more opportunity for receptor diversity and ligand selectivity.

"A big surprise for us seeing the structure was that the ligand was in an extended conformation and pointed perpendicular to the membrane, interacting with the extracellular loops," Stevens said.

This feature can be seen as the rationale for A2A receptor selectivity and may help in the design of new chemical entities with increased selectivity for this important drug target.

Release Date: October 2, 2008
Source: The Scripps Research Institute