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    Home > Biochemistry News > Biotechnology News > Nat Commun Shanghai Institute of Pharmaceutical Sciences collaborated to reveal the G protein selective coupling activation mechanism of class B GPCRs

    Nat Commun Shanghai Institute of Pharmaceutical Sciences collaborated to reveal the G protein selective coupling activation mechanism of class B GPCRs

    • Last Update: 2022-11-14
    • Source: Internet
    • Author: User
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    On November 5, 2022, the team of Xu Huaqiang/Zhao Lihua of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, together with the team of Yu Xiao/Sun Jinpeng of Shandong University, and the team of Zhang Yan of the School of Basic Medicine of Zhejiang University, published a report entitled Structure insights into selective coupling of G protein subtypes by a class B online in Nature Communications The results of the study of
    Gprotein-coupled receptors.
    On the basis of revealing the specific mechanism of two receptor hormone recognition, receptor activation and G protein coupling of a subfamily of class B GPCRs, the researchers successfully analyzed the three-dimensional structure of CRF2R and Go protein and G11 protein complex, respectively, which are the first complex structures of class B GPCRs coupling Go and G11, respectively, and systematically elucidated ACTH-releasing factor receptors coupled to Gs, G11 and G The molecular mechanism of oprotein has laid the foundation for
    the study of the mechanism of selective coupling and activation of G protein in class B GPCRs.

    GPCR is the largest class of cell surface receptor family, with more than 800 members, regulating various life activities of the human body and closely related to diseases, more than 30% of drugs act on GPCR, so GPCR is considered the most important drug target, of which class B GPCR is a class of peptide hormone receptors, including adrenocorticotropic hormone releasing factor (CRF), glucagon (GCG), glucagon-like peptide (GLP), parathyroid hormone (PTH), and other 15 hormone receptors, the signal activation process of class B GPCR receptors through the binding with agonists, coupling downstream G proteins, mainly mediating Gs signaling pathways, but also may mediate Gαi/o, Gαq/11 and other signaling pathways play a wide range of physiological processes from body growth and development to metabolic regulation and bone development, class B G protein-coupled receptors (GPCRs) family plays a key role in hormonal hormone balance, is a major human disease, such as cancer, Important drug targets for diabetes, depression, cardiovascular disease, and osteoporosis
    Therefore, understanding the mechanism of selective G protein coupling activation of class B GPCRs is an important scientific problem
    in the field of class B GPCRs.

    Corticotropin-Releasing Factor Receptors CRF1R and CRF2R are important members of class B GPCRs, two different subclasses that play an important role in the central and peripheral nervous systems, and are important drug targets
    for anxiety, depression and cardiovascular disease 。 The teams of Xu Huaqiang/Zhao Lihua/Zhang Yan published in Molecular Cell in 2020 the high-resolution three-dimensional structure
    of CRF1R and CRF2R with Gs protein trimer complexes under the activation of endogenous ligand UCN1.
    The specific mechanism of ligand recognition of different receptors has been revealed, providing a strong structural basis
    for drug development targeting stress response, anxiety, depression and cardiovascular and cerebrovascular diseases.
    At the same time, Yu Xiao/Gong Yaoqin/Sun Jinpeng's team also participated in J Clin.
    published an article showing that UCN3, secreted by islet β cells, maintains islet function homeostasis by activating CRF2R on islet δ cells, forming the UCN3-CRF2R signal axis of the islet endogenous cell circuit, and by regulating the CUL4B/PRC2 epigenetic complex
    Abnormal blocking of the islet endogenous UCN3-CRF2R pathway can lead to the development of diabetes, and the mechanism and function of UCN3-CRF2R downstream coupling to G protein isoforms are unknown

    On the basis of the previous one, the research team used single-particle cryo-EM technology to analyze the structure of UCN1-CRF2R-Go and UCN1-CRF2R-G11 complexes with resolutions of 2.
    8 angstroms and 3.
    7 angstroms, respectively (Fig.
    1a-c), compared the area size of the binding interface of different G proteins (Gs, Go and G11) in CRF2R and the size of the C-terminal amino acid side chain of the α5 helix of Gα, and found that the side chain in the C-terminal amino acid Gs protein was the largest.
    The largest binding area and the most interaction with the receptor are formed, followed by G11 protein, and finally Go protein, which is consistent with the ability of class B GPCRs to couple different G proteins, Gs > Gq/11> Gi/o, revealing that the C-terminus of the α5 helix of Gα plays a decisive role in CRF2R selectively coupling different G proteins (Figure 1d-i).

    。 The characteristics of all currently resolved activated conformational class B GPCRs that are different from class A GPCRs are that they will be bent outward at approximately 90 degrees in the middle of TM6, thereby forming a large binding pocket on the cytosolic side, which is conducive to the binding of G proteins, and this large binding pocket can form extensive interactions with the maximum Gs protein of the C-terminal amino acid side chain, which better explains the molecular basis of the classical signaling pathway Gs protein coupling in the class B GPCRs family.
    At the same time, it also fills the research gap
    of class B GPCRs in the mechanism of G11 and GO signaling pathways.

    1 Cryo-EM structure of CRF2R coupled to different G proteins and molecular mechanism of selective coupling to G proteins

    This study was completed
    by the research team of Xu Huaqiang/Zhao Lihua of Shanghai Institute of Materia Medica, the team of Yu Xiao/Sun Jinpeng of Shandong University, and the team of Zhang Yan of the School of Basic Medicine of Zhejiang University, and the assistance of Professor Karsten Melcher of the Wen'anluo Institute in the United States.
    Zhao Lihua, researcher of Shanghai Institute of Materia Medica, Lin Jingyu of Shandong University, Suyu Hao, Zhejiang University, and X.
    Edward Zhou is co-first author
    of the paper.
    Researcher Xu Huaqiang, researcher Zhao Lihua, Professor Yu Xiao and researcher Zhang Yan are the co-corresponding authors
    Also involved in this work are Dr.
    He Xinheng of Shanghai Institute of Materia Medica, Professor Xiao Peng of Shandong University, Mao Youchun of Zhejiang University, Shen Dandan and Professor
    Karsten Melcher of the Wen'anluo Institute of the United States.
    This work has been supported
    by the Youth Innovation Promotion Association of the Chinese Academy of Sciences, the National Key Research and Development Program, the Shanghai Municipal Science and Technology Commission, and the National Natural Science Foundation of China.
    The cryo-EM data in this study were collected
    on the cryo-EM platform of Shanghai Institute of Materia Medica, and the electron microscopy platform of Zhejiang University.

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    (Contributing department: Xu Huaqiang research group; Contributor: Zhao Lihua)

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