Protein "3D photo" is expected to make future medicine "one stone counts birds"

At the beginning of the 2018 new year, ihuman Research Institute of Shanghai University of science and technology made another major breakthrough in the field of human cell signal transduction The team took the lead in analyzing the three-dimensional fine structure of the human serotonin 2C receptor (5-HT2C), a target closely related to obesity and mental diseases, and revealed the molecular mechanism of multiple pharmacology of the G protein coupled receptor (GPCR) family, an important member of human cell signal transduction This research achievement is entitled "5-HT2C receiver structures reveal the structural basis of GPCR polypharmacology" and published online in the top international academic journal Cell It is worth mentioning that this research is another major breakthrough after ihuman Institute of Shanghai University of science and technology first published the high-resolution three-dimensional structure of cannabinoid receptor and glucagon like peptide receptor in 2016 and 2017, and it is another high-level and systematic research achievement in the field of GPCR structure and function research Peng Yao, a Ph.D student jointly trained by Shanghai University of science and technology and Institute of Biophysics, Chinese Academy of Sciences, is the first author of the paper Professor Liu Zhijie, executive director of ihuman Research Institute, Raymond Stevens, founding director and distinguished professor, and Professor Bryan Roth, University of North Carolina are the co authors of the paper Shangke university is the first completion unit There are many G-protein-coupled receptors on the surface of human cells, whose functions are equivalent to "signal soldiers" of cells These "signal soldiers" are responsible for the information exchange between cells, and then widely participate in the regulation of human physiological or pathological state They are closely related to people's daily life - for example, the eyes can see the bright sunshine, the nose can smell the fragrance of flowers, the tongue can taste the ups and downs of food, and their disorders will lead to the occurrence of diseases Therefore, GPCR is the "Darling" in the field of drug research and development At present, more than 40% of drugs on sale are targeted at GPCR GPCR family members have a very conservative seven times of transmembrane helix structure After the ligand binds to the receptor, the information is transmitted to the cell through the conformational change of transmembrane region The properties of ligands determine the state of GPCR: the activating ligand (agonist) activates the receptor, while the inhibiting ligand (antagonist) inhibits the activity of the receptor The three-dimensional structure of the receptor after binding with these two kinds of ligands can be said to be the "dynamic and static two sides" of the receptor For different GPCR, agonist or antagonist ligands have different drug development value As a member of GPCR family, serotonin 2C receptor (5-HT2C) is responsible for regulating many important physiological and psychological states such as mood, appetite, sleep, pain, addiction and memory At present, there are drugs for serotonin 2C receptor on the market For example, chloranthine is a weight-loss drug approved by the US FDA Serotonin 2C receptor is also a potential drug target for depression, schizophrenia, drug addiction and other mental diseases However, the research and development of drugs based on serotonin 2C receptor is not smooth Many small molecule drugs with good therapeutic effect have different degrees of side effects due to the Miss target effect For example, the weight-loss drug chloranthine can also act on other targets and lead to the occurrence of heart valve disease The main reason is that the similarity between the members of the serotonin receptor family is very high, which makes it impossible for the drug to accurately identify its target This phenomenon often occurs in other targeted drugs, and becomes the pain point of drug development Therefore, in view of GPCR needs to adopt different strategies according to the actual situation in drug design: one is to make the drug highly selective, that is, one drug only acts on one target ("one stone, one bird"), which helps to avoid the side effects of the drug, which is also the scheme adopted by traditional drug design; the other is to make the drug have multiple drug rationalities, that is, one drug has more effects On the required targets ("one stone counts birds"), while avoiding the side effect targets cleverly, improve the efficacy of drugs in treating complex diseases The drug development strategy of "one stone and several birds" is mainly used to solve complex diseases, such as mental diseases regulated by multiple targets In view of this, in June 2014, ihuman research team decided to explore the structural basis of multiple pharmacological drug design with serotonin 2C receptor as the research object In the next two and a half years, the research team overcame many difficulties After more than 200 cloning and construction, multiple protein expression systems and purification conditions, crystallization optimization and data collection experiments, the team finally analyzed the two different state receptor structures of the combination of agonists and antagonists By obtaining the "3D photo" (fine 3D structure) of the combination of serotonin 2C receptor and two different drug molecules, the researchers first revealed the molecular mechanism of the multiple pharmacological properties of agonists ("one stone, several birds") and the high selectivity of antagonists ("one stone, one bird") on a GPCR It provides a theoretical basis for the design of more accurate targeted drugs for different needs It is worth mentioning that this is the first time in the world to obtain the three-dimensional structure of serotonin receptor in the antagonistic state "There are more than 800 G-protein-coupled receptors in human body, but up to now, only about 50 new structures of GPCR have been resolved Before that, only two serotonin receptor structures were resolved, and all of them were dynamic Peng Yao, the first author of the paper, said: "after unremitting efforts, we finally get two kinds of receptor structures in the same day, which are excited and antagonistic There is a sense of dream come true This pair of receptor structure is like a person with a completely different dual character By analyzing and comparing the two structures and functions, we can provide valuable information for us to further study the interaction mechanism between serotonin 2C receptor and drug molecules " "By analyzing the crystal structure and the pharmacological effects of two different ligands, we proposed the idea of multiple rational drug design for G protein coupled receptor structure It is believed that this kind of attempt will have a very good enlightening significance for drug research and development in the future " Professor Liu Zhijie of ihuman Institute said "Our understanding of G-protein-coupled receptor's multiple rational molecular mechanism is still in its infancy, and there are still many problems to be solved in the process of multi pharmacological drug design for complex major diseases It is hoped that the efforts of the research team can promote people's in-depth understanding of GPCR's multiple pharmacological mechanism, and design more magical multi-target drugs for relieving patients' pain, "concluded Professor Raymond Stevens," which will draw a clearer roadmap for the new generation of G-protein-coupled receptor drug design " In this study, David E Gloriam group of Copenhagen University is responsible for structural information analysis, Zhao Suwen group of ihuman Institute is responsible for computational biology, and Cheng Jianjun group is responsible for pharmaceutical chemical analysis The staff of ihuman Institute's gene cloning platform, eukaryotic expression platform, protein purification platform and function research platform provided strong technical support for this research This work is mainly supported by Shanghai municipal government and Shanghai University of science and technology, and supported by NSFC and Ministry of science and technology As an international high-level research institution, ihuman Research Institute of Shanghai University of science and Technology (ihuman Shanghai iTech Edu CN) has gathered a group of domestic and foreign well-known scholars engaged in human cell signal transduction, focusing on the cross-scale and multimodal integrated biological research by integrating multiple research methods In the past two years, the research team led by Professor Liu Zhijie and Professor Raymond Stevens has made breakthroughs in the structure and function research of several important GPCRs Their series of research results on cannabinoid receptor CB1 were published in cell in October 2016 and nature in July 2017, respectively The research results of GLP1, a diabetes related target, were published in nature in May 2017 All kinds of scientific research talents gathered together, together with high-level scientific research platform, rigorous and practical scientific research atmosphere, and open and active academic exchange atmosphere, ihuman, a young Research Institute, has begun to have a good development trend of world-class research institutions On April 15, 2016, the State Council issued the construction plan of Shanghai Science and technology innovation center, which clearly pointed out that Shanghai University of science and technology has an important task in the construction of Zhangjiang comprehensive national science center At present, the university is cooperating with the Scientific Research Institute of Shanghai Branch of Chinese Academy of Sciences and other units to be responsible for or participate in the construction of soft X-ray free electron laser user device, live cell structure and functional imaging line station project, super short laser experimental device, Shanghai light source phase II line station project, construction of lead hard X-ray free electron laser device, and undertake a number of key work in the construction of science and technology innovation center 。 As of January 2018, 157 research groups have been established in five colleges and three research institutes (including ihuman Research Institute) of the University Scientific research work has been carried out in an all-round way High level scientific research achievements such as three-dimensional structure analysis of serotonin 2C receptor are emerging These scientific breakthroughs are also another major achievement of Shanghai Science and technology innovation center in basic scientific research.