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Team Unveils Molecular Structures Key to Blood Clotting

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SOURCE Shanghai Institute of Materia, CAS

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

SHANGHAI, April 30, 2014 /PRNewswire/ -- 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 1st, the scientists provide a detailed map of P2Y12R, a human Gi 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 Shanghai Tech 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), a potential partial agonist (2MeSATP, 3.1 A), and a non-nucleotide P2Y12R reversible antagonist (AZD1283, 2.6 A) 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. Muller 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, Muller, and Jacobson, other authors of the two studies included Beili Wu, Jin Zhang, Kaihua Zhang, Dandan Zhang, Tingting Li, Limin Ma,Wenru Zhang, Huaiyu Yang, Hualiang Jiang of SIMM; Raymond Stevens, Gye Won Han, Vsevolod Katritch, and Vadim Cherezov of TSRI; and Zhan-Guo Gao and Silvia Paoletta of NIH.

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 and 2014CB910400), 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.

About Shanghai Institute of Materia Medica, Chinese Academy of Sciences

The Shanghai Institute of Materia Medica (SIMM) at the Chinese Academy of Sciences emerged from the Institute of Materia Medica of the Peking Academy of Sciences, founded in 1932. By combining basic and applied research in chemistry and biological disciplines, SIMM carries out modern drug discovery. SIMM is also involved in the discovery of new therapeutic targets and carries out comprehensive pre-clinical evaluation of drug candidates, while also promoting commercialization, thereby playing a key role in building China's drug innovation capabilities. For more information, see http://www.simm.cas.cn.

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs about 3,000 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists - including three Nobel laureates - work toward their next discoveries. For more information, see www.scripps.edu.

About the iHuman Institute

The iHuman Institute was founded in 2012 and is located on the campus of Shanghai Tech University in Shanghai, China. The institute is focused on the study of human cell signaling using a combination of state of the art integrative structural biology, cell biology, chemistry, computational chemistry and biology, and the range of imaging technologies from molecule to man. For more information, see http://www.shanghaitech.edu.cn/en/en_iHuman_Overview.asp.

About National Institutes of Health (NIH)

NIH, the U.S.'s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical and translational medical research, and is investigating the causes, treatments and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

About the Pharma-Center Bonn at the Friedrich-Wilhelms-University Bonn, Germany

The University of Bonn was founded in 1818 and is one of the leading institutions of higher education in Germany. It is a full range university with more than 30,000 students. One of the priority research areas is pharma-research. The Pharma-Center Bonn was founded in 2007 as an interdisciplinary Research Center for Innovative Drugs and Pharmacotherapy, integrating basic and translational research. For more information, see www.pharmazentrum.uni-bonn.de.

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 at 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.

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