Research team Wu Beili and Zhao Qiang from Shanghai Institute of medicine, Chinese Academy of Sciences revealed the mechanism of anti cardiovascular drugs by measuring the structure of thromboxane A2 receptor

Recently, the research team of researcher Wu Beili and researcher Zhao Qiang of Shanghai Pharmaceutical Research Institute of Chinese Academy of sciences have made important progress in the research on the structure and function of anti cardiovascular drug targets -- the first time to determine the thromboxane A2 receptor TP The high-resolution three-dimensional structure combined with the two inhibitors reveals the interaction mechanism between the receptor and a variety of drug molecules, which provides an important basis for drug development in the treatment of cardiovascular diseases The research results were published on Nature Chemical Biology (DOI: 10.1038/s41589-018-0170-9) Prostaglandins play a very important biological function in human body, and mediate cell proliferation, differentiation, apoptosis and other important physiological activities In view of the importance of prostaglandins, the 1982 Nobel Prize in physiology or medicine was awarded to three scientists who have made outstanding contributions to the discovery of prostaglandins and related bioactive substances Prostaglandins in human body include prostaglandins PGD2, PGE2, PGF2 α, PGI2 and thromboxane A2, which function by interacting with their prostaglandin receptors Prostaglandin receptor belongs to the lipid receptor family of G-protein-coupled receptor (GPCR) superfamily, in which thromboxane A2 receptor TP plays a key role in the physiological process of platelet aggregation and vascular smooth muscle cell contraction, so it is an important target for the treatment of cardiovascular diseases such as atherosclerosis and hypertension Because the mechanism of action of TP and its ligand is not clear, the development of anti cardiovascular drugs targeting the receptor is slow, and the candidate drug molecules generally have poor specificity and strong side effects This time, the research team of Wu Beili and Zhao Qiang successfully determined the crystal structures of two complexes of TP and non prostaglandin small molecule inhibitors, Ramatroban and DALTROBAN, respectively By using amino acid mutation and ligand binding experiments, and combining the data of the correlation between the structure and activity of the compounds, TP was clarified at the atomic level The fine binding patterns with these two inhibitors indicate the key amino acids in receptor molecules that play a role in ligand recognition Rimatriban and daquban are both TP inhibitors developed as anti cardiovascular drugs However, their development process is not ideal Rimatriban is only approved as a drug for asthma and allergic rhinitis in Japan, while daquban stops in phase III clinical trials The complex structure of TP and these two drug molecules reveals the mechanism of action of these drugs, and provides a high-precision structure template for drug design targeting the receptor, which will greatly promote the follow-up drug optimization and innovation and new drug development, so as to obtain drug molecules with good efficacy and low side effects The structure of the complexes TP Ramatroban and TP DALTROBAN (source: Nature Chemical Biology) team also found that TP receptor has a unique structural feature Its N-terminal region and the second extracellular ring are respectively connected with the third transmembrane helix of the receptor through the disulfide bond, making TP A two-layer "lid" structure was formed at the entrance of the ligand binding pocket This unique structure has never been found in other GPCR structures The "lid" structure cut off the pathway of ligand from extracellular domain of receptor to binding pocket, and it is likely that the ligand will be diverted through the phospholipid bilayer, and enter the ligand binding site from the gap between the first and seventh transmembrane helices on the side of TP receptor molecule This discovery is helpful to further understand the molecular mechanism of TP's biological function, and expand the understanding of ligand recognition and binding mechanism of lipid receptor In order to further explore the mechanism of selective recognition of ligands by TP and other prostaglandin receptors, the team, based on the crystal structure of TP receptor, predicted the key amino acids involved in binding prostaglandin ligands in TP receptor by computer molecular docking simulation for two prostaglandin ligands sq-29548 and U46619 On this basis, the team further confirmed that these key amino acids play an important role in the process of ligand recognition and receptor activation by means of amino acid mutation, ligand binding and cell signal transduction In addition, the team also found that the first and second transmembrane helices of prostaglandin receptors selectively recognize different prostaglandins by binding to the central substituent groups of prostaglandins, while the amino acids interacting with the side chain groups at both ends of prostaglandin molecules mainly regulate the activation of prostaglandin receptors These findings reveal the specific recognition mechanism of TP for different types of drug molecules and the selective mechanism of different prostaglandin receptors for ligands, and promote the in-depth understanding of the signal transduction mechanism of prostaglandin receptor cells, which is of great guiding significance for the design of new drugs with high selectivity The first authors of the research paper are fan Hengxin and Chen Shuanghong, Ph.D students of Shanghai Institute of medicine The participants of the research include Xu Yechun, Dr Han Shuo, Yuan Xiaojing, Zhang Hui, Ph.D students of Shanghai Institute of medicine, and Xia Weiliang, Professor of Shanghai Jiaotong University The research was supported by the Ministry of science and technology, the Chinese Academy of Sciences and the National Natural Science Foundation of China.