Structures of human P2Y₁₂ receptor key to next generation of antithrombotic drugs 

SHANGHAI –May 1, 2014–An international team led by scientists at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences (SIMM) has found the detailed structure of a receptor that plays a key role in platelet activation and blood clotting. The work has implications for treatment of cardiovascular and other diseases. 

In a pair of papers published by the journal Nature on May 1^st, the scientists provide a detailed map of P2Y₁₂R, a human G_i protein-coupled receptor, in the antagonist and agonist bound states. The antithrombotic drug target has a market of several billion U.S. dollars. 

“This new work will not only deepen understanding of activation of this receptor super-family, but will also provide invaluable insight into the improvement and development of P2Y₁₂ drugs targeting cardiovascular and other diseases,” said team leader Qiang Zhao, professor at SIMM. “I was particularly proud of the high quality international collaboration between China, USA, and Germany that it took to complete this research.” 

The structures were solved by SIMM in collaboration with research groups from National Institutes of Health (NIH; United States), The Scripps Research Institute GPCR Network (United States), iHuman Institute of ShanghaiTech University (China) and University of Bonn (Germany). 

"What we've learned from this research could pave the way for the creation of drugs with fewer limitations and health risks," said Dr. Kenneth A. Jacobson, chief of the Laboratory of Bioorganic Chemistry in the National Institute of Diabetes and Digestive and Kidney Diseases at NIH and an author on the paper. "Our discoveries have the potential to make a significant difference in patients' lives." 

Platelet activation and subsequent aggregation to form a thrombus plug are critical for the cessation of blood loss due to vessel damage. Inappropriate activation of platelets after intravascular damage often leads to the formation of a platelet-rich thrombus, which can subsequently result in life-threatening conditions such as unstable angina, heart attack and stroke. 

Laboratory and clinical experience with currently marketed P2Y₁₂R targeting drugs has led to the understanding that each of the drugs has certain limitations, and that efforts to develop better drugs have been impeded by poor understanding of receptor-ligand interaction. 

These studies describe for the first time the three-dimensional structure of the P2Y₁₂R, in complex with a full agonist (2MeSADP at 2.5 ？),a potential partial agonist (2MeSATP, 3.1 ？), and a non-nucleotide P2Y₁₂R reversible antagonist (AZD1283, 2.6 ？)designed by AstraZeneca. Combining the comprehensive knowledge gained from the three structures, the researchers achieved a detailed understanding of recognition of different types of drugs by the receptor to either promote or inhibit platelet aggregation. 

The new studies provide many new insights regarding the structure of the P2Y₁₂R versus that of other recently crystallized GPCRs. Comparing the agonist-bound P2Y₁₂R with an antagonist-bound form, the researchers found that for the agonist and non-nucleotide antagonist to bind to the P2Y₁₂R,the molecules adopt different orientations in the receptor, with only partially overlapped binding pockets. Moreover, agonist access to the binding pocket requires large-scale rearrangements in the extracellular region of the receptor, which could not be predicted. The nucleotide agonist draws inward the normally flexible outer loops, which tighten around the negatively charged phosphate groups.  

"Since there are a number of receptors with similar properties, the research into the P2Y₁₂ receptor gives hope for other applications,” said Professor Christa E. Müller of the University of Bonn in Germany.“Thus, the related P2Y₂ receptor is, for example, involved in the metastasis of tumor cells. Here, too, new options for cancer research could arise."  

In addition to Zhao, Müller, and Jacobson, other authors of the two studies included Beili Wu, Jin Zhang, Kaihua Zhang, Dandan Zhang, Tingting Li, LiminMa,Wenru Zhang, Huaiyu Yang, Hualiang Jiang of SIMM; Gye Won Han, Vsevolod Katritch, and Vadim Cherezov of TSRI; and Zhan-Guo Gao and Silvia PaolettaofNIH. 

The studies, “Agonist-bound structure of the human P2Y12 receptor” and “Structure of the human P2Y12 receptor in complex with an antithrombotic drug,” were funded in part by the National Basic Research Program of China (grants 2012CB518000 2012CB910400 and2014CB910400), NIH (U54 GM094618 and a supplement to U54 GM094618 as part of the U.S.-China Biomedical Collaborative Research Program and the NIH Intramural Research Program), and the National Science Foundation of China (grants 31370729 and 91313000). To view the study, visit http://www.nature.com. 

Figure: The crystal structure and function of the P2Y12 receptor.The receptor structure is shown as a yellow ribbon (bottom). The physiological ligand (ADP, top right-hand side) that stimulates the formation of blood clots, and the drug that suppresses platelet aggregation (AZD1283, top, left-hand side) are shown as coloured molecular stick models within a capsule (AZD1283), or on a blood coagulation thrombus (ADP), respectively.(Image by SIMM)

SIMM hosts the press conference on April 30th(Image by SIMM)

Professor Qiang Zhao answers questions from jounalists(Image by SIMM)

CONTACT INFORMATION 

To request an interview with Professor Qiang Zhao, please contact zhaoq@simm.ac.cn. 

To request an interview with Dr. Jacobson, please contact Krysten Carrera krysten.carrera@nih.gov.The opinions and conclusions are those of the authors and do not necessary reflect the official views of SIMM or NIH.