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Structures of the glucocorticoid-bound adhesion receptor GPR97-G_o complex

机译：糖皮质激素结合粘附受体GPR97-G_O复合物的结构

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摘要

Adhesion G-protein-coupled receptors (GPCRs) are a major family of GPCRs, but limited knowledge of their ligand regulation or structure is available(1-3). Here we report that glucocorticoid stress hormones activate adhesion G-protein-coupled receptor G3 (ADGRG3; also known as GPR97)(4-6), a prototypical adhesion GPCR. The cryo-electron microscopy structures of GPR97-G(o) complexes bound to the anti-inflammatory drug beclomethasone or the steroid hormone cortisol revealed that glucocorticoids bind to a pocket within the transmembrane domain. The steroidal core of glucocorticoids is packed against the 'toggle switch' residue W-6.53, which senses the binding of a ligand and induces activation of the receptor. Active GPR97 uses a quaternary core and HLY motif to fasten the seven-transmembrane bundle and to mediate G protein coupling. The cytoplasmic side of GPR97 has an open cavity, where all three intracellular loops interact with the Go protein, contributing to the high basal activity of GRP97. Palmitoylation at the cytosolic tail of the G(o) protein was found to be essential for efficient engagement with GPR97 but is not observed in other solved GPCR complex structures. Our work provides a structural basis for ligand binding to the seven-transmembrane domain of an adhesion GPCR and subsequent G protein coupling.
机译：粘附G-蛋白偶联受体（GPCR）是GPCR的主要系列，但可以有限了解其配体调节或结构（1-3）。在这里，我们报告糖皮质激素激素激活粘附G-蛋白偶联受体G3（adgrg3;也称为GPR97）（4-6），一种原型粘附GPCR。 GPR97-G（O）复合物的冷冻电子显微镜结构与抗炎药中结合的甲塞洛或类固醇激素皮质醇显示出糖皮质激素与跨膜结构域内的口袋结合。糖皮质激素的甾体核心堆叠在'拨动开关'残留物W-6.53上，感测配体的结合并诱导受体的激活。活性GPR97使用季芯和HLY主题来固定七跨膜束并介导G蛋白偶联。 GPR97的细胞质侧具有开口腔，其中所有三个细胞内环与GO蛋白相互作用，有助于GRP97的高基础活性。发现G（O）蛋白的细胞骨尾部的棕榈酰胺对于与GPR97有效接合，但在其他溶解的GPCR复合结构中未观察到。我们的作品为配体与粘附GPCR和随后的G蛋白偶联的七跨膜结构域结合的配体提供了结构依据。

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  • 来源
    《Nature》 |2021年第7843期|620-626|共7页
  • 作者

    Ping Yu-Qi; Mao Chunyou; Xiao Peng; Zhao Ru-Jia; Jiang Yi; Yang Zhao; An Wen-Tao; Shen Dan-Dan; Yang Fan; Zhang Huibing; Qu Changxiu; Shen Qingya; Tian Caiping; Li Zi-Jian; Li Shaolong; Wang Guang-Yu; Tao Xiaona; Wen Xin; Zhong Ya-Ni; Yang Jing; Yi Fan; Yu Xiao; Xu H. Eric; Zhang Yan; Sun Jin-Peng;

  • 作者单位

    Chinese Acad Sci Shanghai Inst Mat Med Ctr Struct & Funct Drug Targets CAS Key Lab Receptor Res Shanghai Peoples R China|Peking Univ Sch Basic Med Sci Dept Physiol & Pathophysiol Key Lab Mol Cardiovasc Sci Minist Educ Beijing Peoples R China|Shandong Univ Sch Basic Med Sci Dept Biochem & Mol Biol Cheeloo Coll Med Key Lab Expt Teratol Minist Educ Jinan Shandong Peoples R China;

    Zhejiang Univ Sch Med Sir Run Run Shaw Hosp Dept Biophys Hangzhou Peoples R China|Zhejiang Univ Sch Med Sir Run Run Shaw Hosp Dept Pathol Hangzhou Peoples R China|Zhejiang Univ Med Ctr Zhejiang Lab Syst & Precis Med Hangzhou Peoples R China;

    Shandong Univ Sch Basic Med Sci Dept Biochem & Mol Biol Cheeloo Coll Med Key Lab Expt Teratol Minist Educ Jinan Shandong Peoples R China;

    Shandong Univ Sch Basic Med Sci Dept Biochem & Mol Biol Cheeloo Coll Med Key Lab Expt Teratol Minist Educ Jinan Shandong Peoples R China;

    Chinese Acad Sci Shanghai Inst Mat Med Ctr Struct & Funct Drug Targets CAS Key Lab Receptor Res Shanghai Peoples R China;

    Shandong Univ Sch Basic Med Sci Dept Biochem & Mol Biol Cheeloo Coll Med Key Lab Expt Teratol Minist Educ Jinan Shandong Peoples R China;

    Shandong Univ Sch Basic Med Sci Dept Biochem & Mol Biol Cheeloo Coll Med Key Lab Expt Teratol Minist Educ Jinan Shandong Peoples R China;

    Zhejiang Univ Sch Med Sir Run Run Shaw Hosp Dept Biophys Hangzhou Peoples R China|Zhejiang Univ Sch Med Sir Run Run Shaw Hosp Dept Pathol Hangzhou Peoples R China|Zhejiang Univ Med Ctr Zhejiang Lab Syst & Precis Med Hangzhou Peoples R China;

    Shandong Univ Sch Basic Med Sci Dept Biochem & Mol Biol Cheeloo Coll Med Key Lab Expt Teratol Minist Educ Jinan Shandong Peoples R China|Shandong Univ Cheeloo Coll Med Sch Basic Med Sci Key Lab Expt Teratol Minist Educ Dept Physiol Jinan Shandong Peoples R China;

    Zhejiang Univ Sch Med Sir Run Run Shaw Hosp Dept Biophys Hangzhou Peoples R China|Zhejiang Univ Sch Med Sir Run Run Shaw Hosp Dept Pathol Hangzhou Peoples R China|Zhejiang Univ Med Ctr Zhejiang Lab Syst & Precis Med Hangzhou Peoples R China;

    Peking Univ Sch Basic Med Sci Dept Physiol & Pathophysiol Key Lab Mol Cardiovasc Sci Minist Educ Beijing Peoples R China|Shandong Univ Sch Basic Med Sci Dept Biochem & Mol Biol Cheeloo Coll Med Key Lab Expt Teratol Minist Educ Jinan Shandong Peoples R China;

    Zhejiang Univ Sch Med Sir Run Run Shaw Hosp Dept Biophys Hangzhou Peoples R China|Zhejiang Univ Sch Med Sir Run Run Shaw Hosp Dept Pathol Hangzhou Peoples R China|Zhejiang Univ Med Ctr Zhejiang Lab Syst & Precis Med Hangzhou Peoples R China;

    Beijing Inst Life Natl Ctr Prot Sci Beijing Beijing Proteome Res Ctr State Key Lab Prote Beijing Peoples R China|Tsinghua Univ Sch Med Beijing Peoples R China;

    Peking Univ Minist Educ Key Lab Mol Cardiovasc Sci Beijing 10THE Peoples R China;

    Shandong Univ Sch Basic Med Sci Dept Biochem & Mol Biol Cheeloo Coll Med Key Lab Expt Teratol Minist Educ Jinan Shandong Peoples R China;

    Shandong Univ Sch Basic Med Sci Dept Biochem & Mol Biol Cheeloo Coll Med Key Lab Expt Teratol Minist Educ Jinan Shandong Peoples R China;

    Shandong Univ Sch Basic Med Sci Dept Biochem & Mol Biol Cheeloo Coll Med Key Lab Expt Teratol Minist Educ Jinan Shandong Peoples R China;

    Shandong Univ Sch Basic Med Sci Dept Biochem & Mol Biol Cheeloo Coll Med Key Lab Expt Teratol Minist Educ Jinan Shandong Peoples R China;

    Shandong Univ Sch Basic Med Sci Dept Biochem & Mol Biol Cheeloo Coll Med Key Lab Expt Teratol Minist Educ Jinan Shandong Peoples R China;

    Beijing Inst Life Natl Ctr Prot Sci Beijing Beijing Proteome Res Ctr State Key Lab Prote Beijing Peoples R China;

    Shandong Univ Sch Basic Med Sci Dept Pharmacol Key Lab Infect & Immun Shandong Prov Jinan Shandong Peoples R China;

    Shandong Univ Cheeloo Coll Med Sch Basic Med Sci Key Lab Expt Teratol Minist Educ Dept Physiol Jinan Shandong Peoples R China;

    Chinese Acad Sci Shanghai Inst Mat Med Ctr Struct & Funct Drug Targets CAS Key Lab Receptor Res Shanghai Peoples R China;

    Zhejiang Univ Sch Med Sir Run Run Shaw Hosp Dept Biophys Hangzhou Peoples R China|Zhejiang Univ Sch Med Sir Run Run Shaw Hosp Dept Pathol Hangzhou Peoples R China|Zhejiang Univ Med Ctr Zhejiang Lab Syst & Precis Med Hangzhou Peoples R China|Zhejiang Prov Key Lab Immun & Inflammatory Dis Hangzhou Peoples R China|Zhejiang Univ Sch Med MOE Frontier Sci Ctr Brain Res & Brain Machine In Hangzhou Peoples R China;

    Peking Univ Sch Basic Med Sci Dept Physiol & Pathophysiol Key Lab Mol Cardiovasc Sci Minist Educ Beijing Peoples R China|Shandong Univ Sch Basic Med Sci Dept Biochem & Mol Biol Cheeloo Coll Med Key Lab Expt Teratol Minist Educ Jinan Shandong Peoples R China;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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