News Feature | May 2, 2014

Team Reveals Molecular Structure Key To New Antithrombotic Drugs

By Estel Grace Masangkay

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An international research team headed by the scientists at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences (SIMM) reveals the detailed molecular structure of a receptor called P2Y12 that plays a crucial role in blood clotting and platelet activation. The researchers’ work could be used to develop next generation antithrombotic drugs for cardiovascular and other diseases.

The team provided a detailed map of P2Y12R, a human Gi protein-couple receptor, in the antagonist and agonist bound states. Structures of the receptor were solved by SIMM in collaboration with research groups from the National Institutes of Health and The Scripps Research Institute GPCR Network in the U.S., the iHuman Institute of Shanghai Tech University in China, and University of Bonn in Germany.

The studies describe for the first time the 3D structure of the receptor 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 pharma company AstraZeneca. Efforts to develop better drugs have been hampered by poor understanding of the interaction between receptors and ligands. The three structures provided researchers a vehicle to better understand how the receptor recognizes different types of drugs and can promote or inhibit platelet aggregation. Findings show that molecules adopt different orientations in the receptor for the agonist and non-nucleotide antagonist to bind to the P2Y12R. Agonist access to the binding pockets was shown to require large-scale rearrangements in the receptor’s extracellular region and could not be predicted. The discovery will deepen understanding of activation of the receptor super-family and potentially help in the improvement and development of P2Y12 drugs targeting cardiovascular as well as other diseases.

Professor Christa E. Muller of the University of Bonn in Germany, said, “Since there are a number of receptors with similar properties, the research into the P2Y12 receptor gives hope for other applications. Thus, the related P2Y2 receptor is, for example, involved in the metastasis of tumor cells.” Dr. Muller said that new avenues for cancer research could be determined through the P2Y12 research.

The studies were partly funded by the National Basic Research Program of China and were published in the journal Nature.

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