Nature: crystal structure of glucagon receptor determined by Shanghai Institute of medicine reveals the signal transduction mechanism of type B GPCR

Recently, another important progress has been made in the study of the structure and function of G-protein-coupled receptor (GPCR) of Shanghai Institute of medicine, Chinese Academy of Sciences: the first determination of glucagon receptor, The three-dimensional structure of gcgr) full-length protein and peptide ligand complex reveals the specific recognition of gcgr to cell signaling molecules and its activation regulation mechanism This achievement will help us to understand the structural biological basis of the physiological effect of B-type GPCR and accelerate the development of new drugs for the treatment of type 2 diabetes Relevant research papers were published on the top international academic journal Nature on January 4, 2018, Beijing time, and the corresponding authors are researcher Wu Beili and researcher Zhao Qiang GPCR is the largest membrane receptor protein family in human body and plays an important role in cell signal transduction GPCR is closely related to human diseases At present, more than 40% of drugs on the market target GPCR According to its similarity, GPCR can be divided into four types: A, B, C and F Type B GPCR includes many important receptor proteins such as gcgr It is very important to recognize and bind peptide hormones for maintaining hormone balance in vivo These receptors include extracellular domain and transmembrane domain, both of which are involved in the recognition of cell signals Because it is very difficult to obtain stable and complete B-type GPCR protein, especially the complex of B-type GPCR and peptide ligand, its structure research is very challenging Fig 1 The left picture shows the crystal structure of the complex that the full-length gcgr protein binds to the small molecular allosteric modulator nnc0640 and the antagonistic antibody MAb1; the right picture shows the crystal structure of the complex that the full-length gcgr protein binds to the polypeptide ligand nnc1702 Source: gcgr is an important target for the treatment of type 2 diabetes mellitus, which is involved in the regulation of blood glucose homeostasis The lack of structural information not only seriously restricts the understanding of the receptor signal recognition and transduction mechanism, but also greatly affects the research and development of drugs targeting gcgr, so there is no drug on the market at present In 2017, Wu Beili, Wang Mingwei and Jiang Hualiang from Shanghai Institute of medicine, Chinese Academy of Sciences The crystal structure of the complex was analyzed by the three research groups led by them It was the first time that the three-dimensional structure of the full-length B-type GPCR protein was presented at a high resolution level, and the cooperative regulation mechanism of different domains of the receptor on its activation was revealed, A key step was taken to elucidate the mechanism of GPCR B signal transduction After that, the relevant research team of Shanghai Institute of pharmaceutical research, Chinese Academy of Sciences worked together again to solve the problem, and successfully resolved the crystal structure of the complex of full-length gcgr and glucagon analog nnc1702, thus revealing the fine mode of binding of B-type GPCR and peptide ligand "This achievement is another important progress of our research on structure and function of type B GPCR," said researcher Wu Beili, project director The elucidation of the interaction mode between gcgr and peptide ligands is not only helpful to understand the recognition mechanism of B-type GPCR on cell signaling molecules, but also provides the most accurate structural template for drug design targeting gcgr so far, which will greatly promote the development of new drugs for the treatment of type 2 diabetes In previous studies, the team members found that the peptide segments of gcgr connecting extracellular domain and transmembrane domain play a key role in the regulation of receptor activation by interacting with other regions of receptor protein By analyzing the structure of the complex of gcgr and nnc1702, and comparing with the previously resolved full-length gcgr structure, they further found that there was a significant conformational change in the binding peptide of the receptor The secondary structure changed from β folding to α helix, and the relative orientation between the two domains of the receptor changed greatly with the structure migration It can promote the close binding of receptor and peptide ligand and lead to the activation of receptor In addition, the binding peptide can fine regulate the conformation of receptor transmembrane domain through the interaction with the middle region of peptide ligand, and then regulate the activation of receptor Researcher Zhao Qiang, co-author of the paper, said: "this discovery is really amazing Although it only contains 12 amino acids, the linker plays such an important role, which has never been found in the past GPCR structure research, making us have a deeper understanding of the signal regulation mechanism of type B GPCR." Figure 2 Source of combination mode of nnc1702 and gcgr: Nature Based on the complex structure of gcgr and nnc1702, the team also carried out a series of functional studies using receptor ligand competitive binding, computer simulation, double electron resonance and other technical means, clarified the dynamic changes of gcgr conformation in different functional states, and explored the regulatory mechanism of receptor activation in depth The study was strongly supported by several research groups, such as Shanghai Pharmaceutical Research Institute, Fudan University and Shanghai University of science and technology One of the main partners of the project, academician Jiang Hualiang, director of Shanghai Pharmaceutical Research Institute, stressed that "this is not only another significant research achievement made by GPCR research team of Shanghai Pharmaceutical Institute, but also marks the rise of a GPCR research highland in Zhangjiang High Tech Park, the core area of the construction of Shanghai Science and innovation center." The first author of the research paper is Zhang Haonan, a graduate student The main partners of the project are Wang Mingwei, researcher of Shanghai Institute of medicine, Chinese Academy of Sciences, Yang Dehua, Professor Raymond Stevens, ihuman Institute, Shanghai University of science and technology, Steffen reedtz Runge, Ph.D., Novo Nord company, Denmark, Oliver Ernst, Professor, University of Toronto, Canada, Michael, GPCR research alliance, USA Dr Hanson, Dr Yang Linlin of Zhengzhou University and Professor Yang Huaiyu of East China Normal University The research was supported by the Chinese Academy of Sciences, the National Natural Science Foundation of China, the Shanghai Science and technology development fund and the Shanghai Education Commission Paper link: https://www.nature.com/articles/nature25153 brief introduction of Zhao Qiang and Wu Beili: http://sourcedb.simm.cas.cn/zw/zjrc/201111/t2011818_.html http://sourcedb.simm.cas.cn/zw/zjrc/201111/t201111118_.html Zhao Qiang and Wu Beili jointly discuss the source of academic problems: Chinese children's press