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Structures of full-length glycoprotein hormone receptor signalling complexes

机译：全长糖蛋白激素受体信号配合物的结构

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摘要

Luteinizing hormone and chorionic gonadotropin are glycoprotein hormones that are related to follicle-stimulating hormone and thyroid-stimulating hormone(1,2). Luteinizing hormone and chorionic gonadotropin are essential to human reproduction and are important therapeutic drugs(3-6). They activate the same G-protein-coupled receptor, luteinizing hormone-choriogonadotropin receptor (LHCGR), by binding to the large extracellular domain(3). Here we report four cryo-electron microscopy structures of LHCGR: two structures of the wild-type receptor in the inactive and active states; and two structures of the constitutively active mutated receptor. The active structures are bound to chorionic gonadotropin and the stimulatory G protein (G(s)), and one of the structures also contains Org43553, an allosteric agonist(7). The structures reveal a distinct 'push-and-pull' mechanism of receptor activation, in which the extracellular domain is pushed by the bound hormone and pulled by the extended hinge loop next to the transmembrane domain. A highly conserved 10-residue fragment (P10) from the hinge C-terminal loop at the interface between the extracellular domain and the transmembrane domain functions as a tethered agonist to induce conformational changes in the transmembrane domain and G-protein coupling. Org43553 binds to a pocket of the transmembrane domain and interacts directly with P10, which further stabilizes the active conformation. Together, these structures provide a common model for understanding the signalling of glycoprotein hormone receptors and a basis for drug discovery for endocrine diseases.
机译：叶黄素激素和绒毛膜促性腺激素是糖蛋白激素与卵泡刺激激素和甲状腺刺激激素（1,2）有关。叶黄素激素和绒毛膜促性腺激素对人类繁殖至关重要，是重要的治疗药物（3-6）。它们通过与大细胞外结构域（3）结合来激活相同的G蛋白偶联受体丁黄蛋白化激素 - 甘露聚糖蛋白受体（LHCGR）。在这里，我们报告了LHCGR的四种冷冻电子显微镜结构：无活性和活性状态的野生型受体的两个结构;和组成型活性突变受体的两个结构。活性结构与绒毛膜促性腺激素和刺激G蛋白（G（S））结合，并且其中一种结构还含有ORG43553，一个变形激动剂（7）。该结构揭示了受体激活的不同“推挽”机制，其中细胞外结构域被结合的激素推动并被跨膜结构域旁边的延伸铰链环拉动。从细胞外结构域和跨膜结构域之间的界面处的铰链C末端环路的高度保存的10-残基片段（P10）用作拴系的激动剂，以诱导跨膜结构域和G-蛋白偶联的构象变化。 ORG43553与跨膜结构域的袋结合，并直接与P10相互作用，进一步稳定主动构象。这些结构在一起提供了理解糖蛋白激素受体的信号传导的常用模型，以及对内分泌疾病的药物发现的基础。

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  • 来源
    《Nature》 |2021年第7882期|688-692|共5页
  • 作者

    Duan Jia; Xu Peiyu; Cheng Xi; Mao Chunyou; Croll Tristan; He Xinheng; Shi Jingjing; Luan Xiaodong; Yin Wanchao; You Erli; Liu Qiufeng; Zhang Shuyang; Jiang Hualiang; Zhang Yan; Jiang Yi; Xu H. Eric;

  • 作者单位

    Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res Shanghai Peoples R China|Chinese Acad Sci Shanghai Inst Mat Med State Key Lab Drug Res Shanghai Peoples R China|Univ Chinese Acad Sci Beijing Peoples R China;

    Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res Shanghai Peoples R China|Chinese Acad Sci Shanghai Inst Mat Med State Key Lab Drug Res Shanghai Peoples R China|Univ Chinese Acad Sci Beijing Peoples R China;

    Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res Shanghai Peoples R China|Chinese Acad Sci Shanghai Inst Mat Med State Key Lab Drug Res Shanghai Peoples R China;

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

    Univ Cambridge Cambridge Inst Med Res Dept Haematol Cambridge England;

    Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res Shanghai Peoples R China|Chinese Acad Sci Shanghai Inst Mat Med State Key Lab Drug Res Shanghai Peoples R China|Univ Chinese Acad Sci Beijing Peoples R China;

    Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res Shanghai Peoples R China|Chinese Acad Sci Shanghai Inst Mat Med State Key Lab Drug Res Shanghai Peoples R China;

    Tsinghua Univ Sch Med Beijing Peoples R China|Peking Union Med Coll & Chinese Acad Med Sci Dept Cardiol Peking Union Med Coll Hosp Beijing Peoples R China|Tsinghua Univ Tsinghua Peking Ctr Life Sci Beijing Peoples R China;

    Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res Shanghai Peoples R China|Chinese Acad Sci Shanghai Inst Mat Med State Key Lab Drug Res Shanghai Peoples R China;

    Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res Shanghai Peoples R China|Chinese Acad Sci Shanghai Inst Mat Med State Key Lab Drug Res Shanghai Peoples R China;

    Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res Shanghai Peoples R China|Chinese Acad Sci Shanghai Inst Mat Med State Key Lab Drug Res Shanghai Peoples R China;

    Tsinghua Univ Sch Med Beijing Peoples R China|Peking Union Med Coll & Chinese Acad Med Sci Dept Cardiol Peking Union Med Coll Hosp Beijing Peoples R China|Tsinghua Univ Tsinghua Peking Ctr Life Sci Beijing Peoples R China;

    Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res Shanghai Peoples R China|Chinese Acad Sci Shanghai Inst Mat Med State Key Lab Drug Res Shanghai Peoples R China|Univ Chinese Acad Sci Beijing Peoples R China|ShanghaiTech Univ Sch Life Sci & Technol Shanghai Peoples R China;

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

    Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res Shanghai Peoples R China|Chinese Acad Sci Shanghai Inst Mat Med State Key Lab Drug Res Shanghai Peoples R China|Univ Chinese Acad Sci Beijing Peoples R China;

    Chinese Acad Sci Shanghai Inst Mat Med CAS Key Lab Receptor Res Shanghai Peoples R China|Chinese Acad Sci Shanghai Inst Mat Med State Key Lab Drug Res Shanghai Peoples R China|Univ Chinese Acad Sci Beijing Peoples R China|ShanghaiTech Univ Sch Life Sci & Technol Shanghai 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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