Three dimensional structure of key factors in thrombosis determined by Shanghai Pharmaceutical Research Institute for the first time

      Great breakthrough has been made in the field of structural biology of purinergic receptor p2y1r by Shanghai Institute of pharmaceutical research, Chinese Academy of Sciences: the high-resolution three-dimensional structure of the receptor protein has been determined for the first time, and the mechanism of action of p2y1r inhibitor molecules has been revealed, which provides an important basis for the study of new antithrombotic drugs, and will open a new direction for the research and development of G protein coupled receptor (GPCR) drugs in the future Recently, the research results were published online in the form of article in nature, a top international academic journal Thrombotic diseases, including stroke, coronary heart disease, pulmonary embolism and so on, are one of the important diseases that seriously threaten human life and health In the pathogenesis of thrombotic diseases, two important GPCR, purinergic receptors p2y1r and p2y12r, located on the surface of human platelets, are the key factors to stimulate platelet aggregation and lead to thrombosis Inhibition of the activity of these two receptor proteins can effectively alleviate the formation of thrombus, so p2y1r and p2y12r are very important targets of antithrombotic drugs, and the research and development of their inhibitors has become one of the hot spots in the research of medicine At present, the main target of antithrombotic drugs on the market is p2y12r, with an annual sales volume of up to US $1 billion However, these drugs targeting p2y12r have some side effects, such as longer bleeding time, which can cause dyspnea and so on However, the drug targeting p2y1r is still in the research and development stage, and no product has been successfully launched A large number of studies have shown that p2y1r inhibitor can significantly shorten the bleeding time compared with p2y12r inhibitor Therefore, p2y1r is a potential target of new antithrombotic drugs However, due to the lack of structural information of p2y1r, people's understanding of the molecular mechanism of this receptor and inhibitor has been limited, thus restricting the development of targeted p2y1r drugs In 2014, the research team of Shanghai Pharmaceutical Research Institute of Chinese Academy of Sciences successfully analyzed the three-dimensional structure of p2y12r receptor, and revealed the binding mode of purinergic receptor and drug molecules for the first time This time, they further analyzed the three-dimensional structure of p2y1r complexes with nucleotide inhibitor mrs2500 and non nucleotide inhibitor bptu, respectively "P2y1r structure can help us to understand the interaction mechanism between this receptor protein and different drug lead molecules, and help us design new antithrombotic drugs with less side effects and more safety." Wu Beili, a researcher at the Shanghai Institute of medicine, Chinese Academy of Sciences, who led the study, said By analyzing the structure of p2y1r, many important results have been obtained Among them, it is most exciting to find that p2y1r has two completely different drug molecular action sites at the same time, and the mechanism of action of two inhibitors and receptors is significantly different from the traditional cognition of GPCR in the past Although the binding site of mrs2500, a nucleotide inhibitor of p2y1r, is located in the transmembrane helix of receptor protein, there are great differences in shape and location between this site and that of p2y12r "Although the natural ligands of p2y1r and p2y12r are the same nucleotide molecule adenosine diphosphate (ADP), the binding patterns of these two receptor proteins and nucleotide molecules are totally different." "It's amazing how different two GPCRs recognize the same kind of ligands," said Wu These findings fully reflect the diversity of GPCR on cell signal recognition mechanism, and have great guiding significance for us to design highly specific drug molecules for each receptor protein " More surprisingly, unlike all other known GPCR structures, bptu, a non nucleotide inhibitor of p2y1r, acts on the outer surface of receptor protein and is embedded in lipid molecules of cell membrane This is the first time to find a highly selective ligand binding to the outer surface of GPCR, which greatly expands the direction of drug research and development of GPCR in the future "Looking for new drug molecular recognition sites outside the traditional GPCR ligand binding sites may greatly improve drug specificity and reduce its side effects." Zhao Qiang, another director of the study and a researcher at the Shanghai Institute of medicine, Chinese Academy of Sciences, said "These new structures can help drug researchers more accurately and efficiently design new drugs to regulate the function of p2y1r and other similar receptor proteins." Professor Kenneth A Jacobson, chief scientist of the Bioorganic Chemistry Laboratory of the National Institutes of health, Institute of diabetes, digestive system diseases and nephropathy, a co-author of the study, looks forward to this prospect: "this study may also be applied to the treatment of tumors and inflammation."