IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-36170-3.html
   My bibliography  Save this article

Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor

Author

Listed:
  • Jia Duan

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Peiyu Xu

    (Chinese Academy of Sciences)

  • Huibing Zhang

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University School of Medicine
    Zhejiang Provincial Key Laboratory of Immunity and Inflammatory diseases)

  • Xiaodong Luan

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Peking Union Medical College and Chinese Academy of Medical Sciences
    Tsinghua university
    Tsinghua university)

  • Jiaqi Yang

    (Chinese Academy of Sciences)

  • Xinheng He

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Chunyou Mao

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University School of Medicine
    Zhejiang Provincial Key Laboratory of Immunity and Inflammatory diseases)

  • Dan-Dan Shen

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University School of Medicine
    Zhejiang Provincial Key Laboratory of Immunity and Inflammatory diseases)

  • Yujie Ji

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Xi Cheng

    (Chinese Academy of Sciences)

  • Hualiang Jiang

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    Lingang Laboratory
    ShanghaiTech University)

  • Yi Jiang

    (Lingang Laboratory
    ShanghaiTech University)

  • Shuyang Zhang

    (Peking Union Medical College and Chinese Academy of Medical Sciences
    Peking Union Medical College and Chinese Academy of Medical Sciences
    Tsinghua university
    Tsinghua university)

  • Yan Zhang

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University School of Medicine
    Zhejiang Provincial Key Laboratory of Immunity and Inflammatory diseases)

  • H. Eric Xu

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences
    ShanghaiTech University)

Abstract

Follicle stimulating hormone (FSH) is an essential glycoprotein hormone for human reproduction, which functions are mediated by a G protein-coupled receptor, FSHR. Aberrant FSH-FSHR signaling causes infertility and ovarian hyperstimulation syndrome. Here we report cryo-EM structures of FSHR in both inactive and active states, with the active structure bound to FSH and an allosteric agonist compound 21 f. The structures of FSHR are similar to other glycoprotein hormone receptors, highlighting a conserved activation mechanism of hormone-induced receptor activation. Compound 21 f formed extensive interactions with the TMD to directly activate FSHR. Importantly, the unique residue H6157.42 in FSHR plays an essential role in determining FSHR selectivity for various allosteric agonists. Together, our structures provide a molecular basis of FSH and small allosteric agonist-mediated FSHR activation, which could inspire the design of FSHR-targeted drugs for the treatment of infertility and controlled ovarian stimulation for in vitro fertilization.

Suggested Citation

  • Jia Duan & Peiyu Xu & Huibing Zhang & Xiaodong Luan & Jiaqi Yang & Xinheng He & Chunyou Mao & Dan-Dan Shen & Yujie Ji & Xi Cheng & Hualiang Jiang & Yi Jiang & Shuyang Zhang & Yan Zhang & H. Eric Xu, 2023. "Mechanism of hormone and allosteric agonist mediated activation of follicle stimulating hormone receptor," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36170-3
    DOI: 10.1038/s41467-023-36170-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-36170-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-36170-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Qing R. Fan & Wayne A. Hendrickson, 2005. "Structure of human follicle-stimulating hormone in complex with its receptor," Nature, Nature, vol. 433(7023), pages 269-277, January.
    2. Peng Liu & Yaoting Ji & Tony Yuen & Elizabeth Rendina-Ruedy & Victoria E. DeMambro & Samarth Dhawan & Wahid Abu-Amer & Sudeh Izadmehr & Bin Zhou & Andrew C. Shin & Rauf Latif & Priyanthan Thangeswaran, 2017. "Blocking FSH induces thermogenic adipose tissue and reduces body fat," Nature, Nature, vol. 546(7656), pages 107-112, June.
    3. Bryan Faust & Christian B. Billesbølle & Carl-Mikael Suomivuori & Isha Singh & Kaihua Zhang & Nicholas Hoppe & Antonio F. M. Pinto & Jolene K. Diedrich & Yagmur Muftuoglu & Mariusz W. Szkudlinski & Al, 2022. "Autoantibody mimicry of hormone action at the thyrotropin receptor," Nature, Nature, vol. 609(7928), pages 846-853, September.
    4. Jia Duan & Peiyu Xu & Xiaodong Luan & Yujie Ji & Xinheng He & Ning Song & Qingning Yuan & Ye Jin & Xi Cheng & Hualiang Jiang & Jie Zheng & Shuyang Zhang & Yi Jiang & H. Eric Xu, 2022. "Hormone- and antibody-mediated activation of the thyrotropin receptor," Nature, Nature, vol. 609(7928), pages 854-859, September.
    5. Jing Xiong & Seong Su Kang & Zhihao Wang & Xia Liu & Tan-Chun Kuo & Funda Korkmaz & Ashley Padilla & Sari Miyashita & Pokman Chan & Zhaohui Zhang & Pavel Katsel & Jocoll Burgess & Anisa Gumerova & Kse, 2022. "FSH blockade improves cognition in mice with Alzheimer’s disease," Nature, Nature, vol. 603(7901), pages 470-476, March.
    6. Dean P. Staus & Ryan T. Strachan & Aashish Manglik & Biswaranjan Pani & Alem W. Kahsai & Tae Hun Kim & Laura M. Wingler & Seungkirl Ahn & Arnab Chatterjee & Ali Masoudi & Andrew C. Kruse & Els Pardon , 2016. "Allosteric nanobodies reveal the dynamic range and diverse mechanisms of G-protein-coupled receptor activation," Nature, Nature, vol. 535(7612), pages 448-452, July.
    7. Jia Duan & Peiyu Xu & Xi Cheng & Chunyou Mao & Tristan Croll & Xinheng He & Jingjing Shi & Xiaodong Luan & Wanchao Yin & Erli You & Qiufeng Liu & Shuyang Zhang & Hualiang Jiang & Yan Zhang & Yi Jiang , 2021. "Structures of full-length glycoprotein hormone receptor signalling complexes," Nature, Nature, vol. 598(7882), pages 688-692, October.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Dawei Sun & Yonglian Sun & Eric Janezic & Tricia Zhou & Matthew Johnson & Caleigh Azumaya & Sigrid Noreng & Cecilia Chiu & Akiko Seki & Teresita L. Arenzana & John M. Nicoludis & Yongchang Shi & Baome, 2023. "Structural basis of antibody inhibition and chemokine activation of the human CC chemokine receptor 8," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    2. Yi Cheng & Hong Zhu & Jun Ren & Hai-Yan Wu & Jia-En Yu & Lu-Yang Jin & Hai-Yan Pang & Hai-Tao Pan & Si-Si Luo & Jing Yan & Kai-Xuan Dong & Long-Yun Ye & Cheng-Liang Zhou & Jie-Xue Pan & Zhuo-Xian Meng, 2023. "Follicle-stimulating hormone orchestrates glucose-stimulated insulin secretion of pancreatic islets," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    3. Andrew E. Warfield & Pooja Gupta & Madison M. Ruhmann & Quiana L. Jeffs & Genevieve C. Guidone & Hannah W. Rhymes & McKenzi I. Thompson & William D. Todd, 2023. "A brainstem to circadian system circuit links Tau pathology to sundowning-related disturbances in an Alzheimer’s disease mouse model," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    4. Aika Iwama & Ryoji Kise & Hiroaki Akasaka & Fumiya K. Sano & Hidetaka S. Oshima & Asuka Inoue & Wataru Shihoya & Osamu Nureki, 2024. "Structure and dynamics of the pyroglutamylated RF-amide peptide QRFP receptor GPR103," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    5. Tobias Benkel & Mirjam Zimmermann & Julian Zeiner & Sergi Bravo & Nicole Merten & Victor Jun Yu Lim & Edda Sofie Fabienne Matthees & Julia Drube & Elke Miess-Tanneberg & Daniela Malan & Martyna Szpako, 2022. "How Carvedilol activates β2-adrenoceptors," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    6. Jianying Zhu & Qi Zhang & Hui Zhang & Zuoqiang Shi & Mingxu Hu & Chenglong Bao, 2023. "A minority of final stacks yields superior amplitude in single-particle cryo-EM," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    7. Sen Qiao & Samer Alasmi & Amanda Wyatt & Philipp Wartenberg & Hongmei Wang & Michael Candlish & Debajyoti Das & Mari Aoki & Ramona Grünewald & Ziyue Zhou & Qinghai Tian & Qiang Yu & Viktoria Götz & An, 2023. "Intra-pituitary follicle-stimulating hormone signaling regulates hepatic lipid metabolism in mice," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Michael Schoof & Lan Wang & J. Zachery Cogan & Rosalie E. Lawrence & Morgane Boone & Jennifer Deborah Wuerth & Adam Frost & Peter Walter, 2021. "Viral evasion of the integrated stress response through antagonism of eIF2-P binding to eIF2B," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    9. Yiyuan Xia & Yifan Xiao & Zhi-Hao Wang & Xia Liu & Ashfaqul M. Alam & John P. Haran & Beth A. McCormick & Xiji Shu & Xiaochuan Wang & Keqiang Ye, 2023. "Bacteroides Fragilis in the gut microbiomes of Alzheimer’s disease activates microglia and triggers pathogenesis in neuronal C/EBPβ transgenic mice," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    10. Arum Wu & David Salom & John D. Hong & Aleksander Tworak & Kohei Watanabe & Els Pardon & Jan Steyaert & Hideki Kandori & Kota Katayama & Philip D. Kiser & Krzysztof Palczewski, 2023. "Structural basis for the allosteric modulation of rhodopsin by nanobody binding to its extracellular domain," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    11. Thomas Eden & Alessa Z. Schaffrath & Janusz Wesolowski & Tobias Stähler & Natalie Tode & Nathalie Richter & Waldemar Schäfer & Julia Hambach & Irm Hermans-Borgmeyer & Jannis Woens & Camille M. Gall & , 2024. "Generation of nanobodies from transgenic ‘LamaMice’ lacking an endogenous immunoglobulin repertoire," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    12. Baptiste Fischer & Tomasz Uchański & Aidana Sheryazdanova & Simon Gonzalez & Alexander N. Volkov & Elke Brosens & Thomas Zögg & Valentina Kalichuk & Steven Ballet & Wim Versées & Anna A. Sablina & Els, 2024. "Allosteric nanobodies to study the interactions between SOS1 and RAS," Nature Communications, Nature, vol. 15(1), pages 1-10, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36170-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.