IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v12y2021i1d10.1038_s41467-021-26735-5.html
   My bibliography  Save this article

Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren

Author

Listed:
  • Heng Liu

    (University of Pittsburgh)

  • Dapeng Sun

    (University of Pittsburgh)

  • Alexander Myasnikov

    (St. Jude Children’s Research Hospital)

  • Marjorie Damian

    (Université de Montpellier, ENSCM)

  • Jean-Louis Baneres

    (Université de Montpellier, ENSCM)

  • Ji Sun

    (St. Jude Children’s Research Hospital)

  • Cheng Zhang

    (University of Pittsburgh)

Abstract

The hunger hormone ghrelin activates the ghrelin receptor GHSR to stimulate food intake and growth hormone secretion and regulate reward signaling. Acylation of ghrelin at Ser3 is required for its agonistic action on GHSR. Synthetic agonists of GHSR are under clinical evaluation for disorders related to appetite and growth hormone dysregulation. Here, we report high-resolution cryo-EM structures of the GHSR-Gi signaling complex with ghrelin and the non-peptide agonist ibutamoren as an investigational new drug. Our structures together with mutagenesis data reveal the molecular basis for the binding of ghrelin and ibutamoren. Structural comparison suggests a salt bridge and an aromatic cluster near the agonist-binding pocket as important structural motifs in receptor activation. Notable structural variations of the Gi and GHSR coupling are observed in our cryo-EM analysis. Our results provide a framework for understanding GHSR signaling and developing new GHSR agonist drugs.

Suggested Citation

  • Heng Liu & Dapeng Sun & Alexander Myasnikov & Marjorie Damian & Jean-Louis Baneres & Ji Sun & Cheng Zhang, 2021. "Structural basis of human ghrelin receptor signaling by ghrelin and the synthetic agonist ibutamoren," Nature Communications, Nature, vol. 12(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26735-5
    DOI: 10.1038/s41467-021-26735-5
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-021-26735-5
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-021-26735-5?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. Dollada Srisai & Terry C. Yin & Abigail A. Lee & Alix A. J. Rouault & Nicole A. Pearson & Justin L. Grobe & Julien A. Sebag, 2017. "MRAP2 regulates ghrelin receptor signaling and hunger sensing," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    2. Yuki Shiimura & Shoichiro Horita & Akie Hamamoto & Hidetsugu Asada & Kunio Hirata & Misuzu Tanaka & Kenji Mori & Tomoko Uemura & Takuya Kobayashi & So Iwata & Masayasu Kojima, 2020. "Structure of an antagonist-bound ghrelin receptor reveals possible ghrelin recognition mode," Nature Communications, Nature, vol. 11(1), pages 1-9, December.
    3. Hideaki E. Kato & Yan Zhang & Hongli Hu & Carl-Mikael Suomivuori & Francois Marie Ngako Kadji & Junken Aoki & Kaavya Krishna Kumar & Rasmus Fonseca & Daniel Hilger & Weijiao Huang & Naomi R. Latorraca, 2019. "Conformational transitions of a neurotensin receptor 1–Gi1 complex," Nature, Nature, vol. 572(7767), pages 80-85, August.
    4. Simonas Masiulis & Rooma Desai & Tomasz Uchański & Itziar Serna Martin & Duncan Laverty & Dimple Karia & Tomas Malinauskas & Jasenko Zivanov & Els Pardon & Abhay Kotecha & Jan Steyaert & Keith W. Mill, 2019. "Author Correction: GABAA receptor signalling mechanisms revealed by structural pharmacology," Nature, Nature, vol. 566(7744), pages 8-8, February.
    5. Simonas Masiulis & Rooma Desai & Tomasz Uchański & Itziar Serna Martin & Duncan Laverty & Dimple Karia & Tomas Malinauskas & Jasenko Zivanov & Els Pardon & Abhay Kotecha & Jan Steyaert & Keith W. Mill, 2019. "GABAA receptor signalling mechanisms revealed by structural pharmacology," Nature, Nature, vol. 565(7740), pages 454-459, January.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Jun Xu & Qinggong Wang & Harald Hübner & Yunfei Hu & Xiaogang Niu & Haoqing Wang & Shoji Maeda & Asuka Inoue & Yuyong Tao & Peter Gmeiner & Yang Du & Changwen Jin & Brian K. Kobilka, 2023. "Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    2. Yan Chen & Qingtong Zhou & Jiang Wang & Youwei Xu & Yun Wang & Jiahui Yan & Yibing Wang & Qi Zhu & Fenghui Zhao & Chenghao Li & Chuan-Wei Chen & Xiaoqing Cai & Ross A .D. Bathgate & Chun Shen & H. Eri, 2023. "Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

    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. Shaotong Zhu & Akshay Sridhar & Jinfeng Teng & Rebecca J. Howard & Erik Lindahl & Ryan E. Hibbs, 2022. "Structural and dynamic mechanisms of GABAA receptor modulators with opposing activities," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Nathan L. Absalom & Vivian W. Y. Liao & Katrine M. H. Johannesen & Elena Gardella & Julia Jacobs & Gaetan Lesca & Zeynep Gokce-Samar & Alexis Arzimanoglou & Shimriet Zeidler & Pasquale Striano & Pierr, 2022. "Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Dagimhiwat H. Legesse & Chen Fan & Jinfeng Teng & Yuxuan Zhuang & Rebecca J. Howard & Colleen M. Noviello & Erik Lindahl & Ryan E. Hibbs, 2023. "Structural insights into opposing actions of neurosteroids on GABAA receptors," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Weronika Chojnacka & Jinfeng Teng & Jeong Joo Kim & Anders A. Jensen & Ryan E. Hibbs, 2024. "Structural insights into GABAA receptor potentiation by Quaalude," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    5. Nikhil Bharambe & Zhuowen Li & David Seiferth & Asha Manikkoth Balakrishna & Philip C. Biggin & Sandip Basak, 2024. "Cryo-EM structures of prokaryotic ligand-gated ion channel GLIC provide insights into gating in a lipid environment," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    6. Vikram Dalal & Mark J. Arcario & John T. Petroff & Brandon K. Tan & Noah M. Dietzen & Michael J. Rau & James A. J. Fitzpatrick & Grace Brannigan & Wayland W. L. Cheng, 2024. "Lipid nanodisc scaffold and size alter the structure of a pentameric ligand-gated ion channel," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    7. Arvind Kumar & Kayla Kindig & Shanlin Rao & Afroditi-Maria Zaki & Sandip Basak & Mark S. P. Sansom & Philip C. Biggin & Sudha Chakrapani, 2022. "Structural basis for cannabinoid-induced potentiation of alpha1-glycine receptors in lipid nanodiscs," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    8. Marie S. Prevost & Nathalie Barilone & Gabrielle Dejean de la Bâtie & Stéphanie Pons & Gabriel Ayme & Patrick England & Marc Gielen & François Bontems & Gérard Pehau-Arnaudet & Uwe Maskos & Pierre , 2023. "An original potentiating mechanism revealed by the cryo-EM structures of the human α7 nicotinic receptor in complex with nanobodies," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    9. Xiuwen Zhai & Chunyou Mao & Qingya Shen & Shaokun Zang & Dan-Dan Shen & Huibing Zhang & Zhaohong Chen & Gang Wang & Changming Zhang & Yan Zhang & Zhihong Liu, 2022. "Molecular insights into the distinct signaling duration for the peptide-induced PTH1R activation," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    10. Hiroaki Akasaka & Tatsuki Tanaka & Fumiya K. Sano & Yuma Matsuzaki & Wataru Shihoya & Osamu Nureki, 2022. "Structure of the active Gi-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    11. Mark J. Wall & Emily Hill & Robert Huckstepp & Kerry Barkan & Giuseppe Deganutti & Michele Leuenberger & Barbara Preti & Ian Winfield & Sabrina Carvalho & Anna Suchankova & Haifeng Wei & Dewi Safitri , 2022. "Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    12. Fabian Bumbak & James B. Bower & Skylar C. Zemmer & Asuka Inoue & Miquel Pons & Juan Carlos Paniagua & Fei Yan & James Ford & Hongwei Wu & Scott A. Robson & Ross A. D. Bathgate & Daniel J. Scott & Pau, 2023. "Stabilization of pre-existing neurotensin receptor conformational states by β-arrestin-1 and the biased allosteric modulator ML314," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    13. Na Wang & Xinheng He & Jing Zhao & Hualiang Jiang & Xi Cheng & Yu Xia & H. Eric Xu & Yuanzheng He, 2022. "Structural basis of leukotriene B4 receptor 1 activation," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    14. Yatabe, Zenji & Asubar, Joel T., 2021. "Ornstein–Uhlenbeck process in a human body weight fluctuation," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 582(C).
    15. Wenli Zhao & Wenru Zhang & Mu Wang & Minmin Lu & Shutian Chen & Tingting Tang & Gisela Schnapp & Holger Wagner & Albert Brennauer & Cuiying Yi & Xiaojing Chu & Shuo Han & Beili Wu & Qiang Zhao, 2022. "Ligand recognition and activation of neuromedin U receptor 2," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    16. Yan Chen & Qingtong Zhou & Jiang Wang & Youwei Xu & Yun Wang & Jiahui Yan & Yibing Wang & Qi Zhu & Fenghui Zhao & Chenghao Li & Chuan-Wei Chen & Xiaoqing Cai & Ross A .D. Bathgate & Chun Shen & H. Eri, 2023. "Ligand recognition mechanism of the human relaxin family peptide receptor 4 (RXFP4)," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    17. Chongzhao You & Yumu Zhang & Peiyu Xu & Sijie Huang & Wanchao Yin & H. Eric Xu & Yi Jiang, 2022. "Structural insights into the peptide selectivity and activation of human neuromedin U receptors," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    18. Chaehee Park & Jinuk Kim & Seung-Bum Ko & Yeol Kyo Choi & Hyeongseop Jeong & Hyeonuk Woo & Hyunook Kang & Injin Bang & Sang Ah Kim & Tae-Young Yoon & Chaok Seok & Wonpil Im & Hee-Jung Choi, 2022. "Structural basis of neuropeptide Y signaling through Y1 receptor," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    19. Youwen Zhuang & Lei Wang & Jia Guo & Dapeng Sun & Yue Wang & Weiyi Liu & H. Eric Xu & Cheng Zhang, 2022. "Molecular recognition of formylpeptides and diverse agonists by the formylpeptide receptors FPR1 and FPR2," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    20. Chunyou Mao & Mengru Gao & Shao-Kun Zang & Yanqing Zhu & Dan-Dan Shen & Li-Nan Chen & Liu Yang & Zhiwei Wang & Huibing Zhang & Wei-Wei Wang & Qingya Shen & Yanhui Lu & Xin Ma & Yan Zhang, 2023. "Orthosteric and allosteric modulation of human HCAR2 signaling complex," Nature Communications, Nature, vol. 14(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:12:y:2021:i:1:d:10.1038_s41467-021-26735-5. 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.