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    Home > Medical News > Latest Medical News > Heavy! The Shi's team then solved the important protein structure of Alzheimer's

    Heavy! The Shi's team then solved the important protein structure of Alzheimer's

    • Last Update: 2020-12-31
    • Source: Internet
    • Author: User
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    0:00 a.m. Beijing time on December 29, 2020, Cell published a new study by Shi Igong, a
    academician and president of West Lake University.study first reported the molecular mechanism of γ-secretase (γ-secretase) in combination with three small molecule inhibitors (Gamma-Secretase Inhibitor, GSI) and one regulator (Gamma-Secretase Modulator, GSM) for four atomic resolution cryoscopics, clarifying the molecular mechanism of γ-secretases to identify different types of inhibitors and regulators.
    This study is the first to fully demonstrate the entire process of γ-secretase binding substrates and drugs, providing an unprecedentedly accurate blueprint for understanding the mechanism of γ-secretase activity regulation, and will greatly advance the design and optimization of the next generation of γ-secretase inhibitors and regulators.
    Yang Guangguang, the first author of the paper and a former distinguished scholar at Tsinghua University's Center for Structural Biology and now a professor at the China Agricultural University, told the China Science Journal that the work will provide important structural information for the study of Alzheimer's disease and cancer-related substrate-selective γ-secretase inhibitors.
    Alzheimer's disease is the most widespread and serious neurodegenerative disease in the world today, and so far there are no specific drugs.
    "γ secretion enzyme is a protease, its function is to cut or hydrolyze other proteins, amyloid protein is one of its hydrolysis objects, this protein plaque deposits and Alzheimer's disease is very closely related. Yang told China Science Daily. Scientists have long developed disease treatment strategies around the principle of amyloid plaque deposition, a specific marker in Alzheimer's patients, and many drug developments for Alzheimer's have directly targeted γ-secretases in the hope of treating the disease by regulating its activity.
    history, γ-secretase as a target drug has also entered clinical Phase II or Phase III trials, but all ended in failure. Among them, the first γ-secretase inhibitor small molecule drug Semagacestat into clinical Phase III trial results show that drug use has not slowed the development of the disease, according to the paper's co-author, Tsinghua University School of Life Assistant Researcher Zhou Rui, "Semagacestat not only led to cognitive and daily activity of patients weakened, but also increased the risk of skin cancer patients." "The reason for this is most likely that this inhibitor inhibits the cutting of THEP, as well as the cutting of Notch, another important substrate of γ-secretion enzymes.
    In the latest study, researchers first analyzed the 3.0-E resolution structure of γ-secretase and its inhibitor Semagacestat and found that the "bit resistance" formed by Semagacestat was the mechanism by which it inhibited and produced side effects.
    , the researchers analyzed γ structure of 3.1 E in combination with another inhibitor, Avagacestat. Avagacestat was developed by BMS and is now in clinical Phase II trials.
    " results were unexpected, with Avagacestat in a position that is almost consistent with Semagacestat, and there is also a 'bit resistance', but its interactions take on a more 'loose' state. "This suggests that Avagacestat's substrate selectivity may have something to do with the differences in these forms of interaction, " Yang told China Science Daily. "At the same time, to provide a more comprehensive picture of the role of all types of inhibitors, the researchers further analyzed the structure of the γ-secretase binding transition state similar (TSA) inhibitor L685,458.
    This study reveals the workings of three different γ-secretase inhibitors, analyzes their commonalities and, more importantly, reveals the differences between the three, and lays a solid foundation for future optimization and design of substrate-specific inhibitors.In addition, the researchers analyzed the relevant frozen electroscope structure with a resolution of up to 2.6 E, providing structural information for a more complete understanding of the γ-secretase activity regulator γ (GSMs).
    ShiIgong Laboratory has been working to reveal the pathogenesis of Alzheimer's disease, γ-secretase 3D structure and the analysis of its workings is an important direction, over the years in Nature, Science, Cell and other journals published a number of research results with this protease as the core.
    the pre-laboratory human source γ-secretase and γ-secretase binding important substrate cryoscopy structure research for today's publication of γ-secretase drug regulatory structure laid a good foundation, they are a layer-by-layer step-by-step relationship between the structure of the previous substrate, the results of this results more clearly revealed how these regulators and inhibitors inhibit the entry of the substrate, for the previous clinical drug failure provides an explanation for the field of an important foundation. Zhou Rui said that the team will further research on Alzheimer's disease in the fields of γ-secretion enzyme activity regulation, amyloid precipitation, Tau protein, and so on.
    it is understood that Shi Yigong is the co-author of the research paper, Yang Guangguang and Zhou Rui, a third-year doctoral student at Tsinghua University's School of Life, guo Xuefei, are co-authors of the paper.
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