Scientists from The Scripps Research Institute have determined the structure of a new neurological receptor, A2A adenosine receptor, from within a larger group of four GPCRs that play an essential role in the central nervous system in pain regulation, cerebral blood flow, basal ganglia functions, respiration, and sleep.
Since GPCRs are critical for almost all aspects of health and disease, the research team previously figured out the structure of the b2-adrenergic GPCR with multiple ligands. The crystallographic model of the A2A receptor bound to ZM241385, however, reveals features distinct from previously reported GPCR structures. The findings could help develop treatments for neurological disorders such as Parkinson’s and Huntington diseases.
In the new study, investigators worked to illuminate the A2A adenosine receptor. This receptor is blocked by methylxanthines such as caffeine, which prevent 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 high-affinity antagonist ZM241385, which stabilizes the receptor and had been developed as a potential drug to combat Parkinson’s disease.
Once the two molecules were bound together, the scientists were able to obtain crystals of the complex and determine its structure. The 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,” said Raymond Stevens, Ph.D., a Scripps Research scientist and professor.