Stroke, coronary heart disease and pulmonary embolism are serious threats to human health and are common causes of death. In these “thrombotic” diseases, a molecule called purinergic receptor P2Y₁₂ is an important factor in the formation of blood clots (thrombus), and thus compounds that act on P2Y₁₂ receptors are one of the hotspots of drug development. Even though several FDA-approved P2Y₁₂-targeting drugs are already on the market, their side effects suggest that better drugs are still in great need. Until now, however, these efforts have been limited by poor structural and biochemical knowledge of P2Y₁₂.

Dr. ZHAO Qiang  and Dr.WU Beili from Shanghai Institute of Material Medica (SIMM), together with research groups from National Institutes of Health (NIH) in Maryland (United States), The Scripps Research Institute in California (United States), iHuman Institute of ShanghaiTech University and Bonn University (Germany), have determined the high-resolution crystal structure of the P2Y₁₂ receptor in complex with an antithrombotic drug.

The findings were published online ahead of print by the journal Nature on March 23, 2014.

The study reveals many distinct features of P2Y₁₂ that set the structure apart from all other known GPCRs, expanding scientists’ knowledge of this receptor superfamily. Along with uncovering new details of the structure—including two different binding pockets—the scientists conducted a series of computational biology and functional experiments that demonstrate how different drugs interact with the receptor via different domains of the binding site.

"This paper clearly addresses a very important question,” said peer reviewers of this paper. “P2Y₁₂ receptor is a major drug target, mediating platelet aggregation and thrombus formation. The three-dimensional structure of the P2Y₁₂ receptor may help chemists to develop new drugs that are effective on a large population and with reduced side effects. There is a multibillion-dollar market for these drugs, so new insight that might help therapeutic development is valuable.”

The study, “Structure of the human P2Y₁₂ receptor in complex with an antithrombotic drug,” was funded in part by the National Basic Research Program of China (grants 2012CB518000 and 2012CB910400), the National Institutes of Health (R01 AI100604, U54 GM094618 and a supplement to U54 GM094618 as part of the U.S.-China Biomedical Collaborative Research Program), the National Science Foundation of China (grants 31270766, 81161120425, and 81025017). To view the study, visit http://www.nature.com.