IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-34696-6.html
   My bibliography  Save this article

Activation and signaling mechanism revealed by GPR119-Gs complex structures

Author

Listed:
  • Yuxia Qian

    (Tianjin University)

  • Jiening Wang

    (Hubei University)

  • Linlin Yang

    (Zhengzhou University)

  • Yanru Liu

    (Tianjin University)

  • Lina Wang

    (Zhengzhou University)

  • Wei Liu

    (Tianjin University)

  • Yun Lin

    (Tianjin University)

  • Hong Yang

    (Hubei University)

  • Lixin Ma

    (Hubei University)

  • Sheng Ye

    (Tianjin University
    Zhejiang University)

  • Shan Wu

    (Hubei University)

  • Anna Qiao

    (Tianjin University)

Abstract

Agonists selectively targeting cannabinoid receptor-like G-protein-coupled receptor (GPCR) GPR119 hold promise for treating metabolic disorders while avoiding unwanted side effects. Here we present the cryo-electron microscopy (cryo-EM) structures of the human GPR119-Gs signaling complexes bound to AR231453 and MBX-2982, two representative agonists reported for GPR119. The structures reveal a one-amino acid shift of the conserved proline residue of TM5 that forms an outward bulge, opening up a hydrophobic cavity between TM4 and TM5 at the middle of the membrane for its endogenous ligands-monounsaturated lipid metabolites. In addition, we observed a salt bridge between ICL1 of GPR119 and Gβs. Disruption of the salt bridge eliminates the cAMP production of GPR119, indicating an important role of Gβs in GPR119-mediated signaling. Our structures, together with mutagenesis studies, illustrate the conserved binding mode of the chemically different agonists, and provide insights into the conformational changes in receptor activation and G protein coupling.

Suggested Citation

  • Yuxia Qian & Jiening Wang & Linlin Yang & Yanru Liu & Lina Wang & Wei Liu & Yun Lin & Hong Yang & Lixin Ma & Sheng Ye & Shan Wu & Anna Qiao, 2022. "Activation and signaling mechanism revealed by GPR119-Gs complex structures," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34696-6
    DOI: 10.1038/s41467-022-34696-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-34696-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-34696-6?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. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
    2. Hui-Woog Choe & Yong Ju Kim & Jung Hee Park & Takefumi Morizumi & Emil F. Pai & Norbert Krauß & Klaus Peter Hofmann & Patrick Scheerer & Oliver P. Ernst, 2011. "Crystal structure of metarhodopsin II," Nature, Nature, vol. 471(7340), pages 651-655, March.
    3. Tian Hua & Kiran Vemuri & Spyros P. Nikas & Robert B. Laprairie & Yiran Wu & Lu Qu & Mengchen Pu & Anisha Korde & Shan Jiang & Jo-Hao Ho & Gye Won Han & Kang Ding & Xuanxuan Li & Haiguang Liu & Michae, 2017. "Crystal structures of agonist-bound human cannabinoid receptor CB1," Nature, Nature, vol. 547(7664), pages 468-471, July.
    4. John Jumper & Richard Evans & Alexander Pritzel & Tim Green & Michael Figurnov & Olaf Ronneberger & Kathryn Tunyasuvunakool & Russ Bates & Augustin Žídek & Anna Potapenko & Alex Bridgland & Clemens Me, 2021. "Highly accurate protein structure prediction with AlphaFold," Nature, Nature, vol. 596(7873), pages 583-589, August.
    5. A. J. Venkatakrishnan & Xavier Deupi & Guillaume Lebon & Christopher G. Tate & Gebhard F. Schertler & M. Madan Babu, 2013. "Molecular signatures of G-protein-coupled receptors," Nature, Nature, vol. 494(7436), pages 185-194, February.
    6. Andrew C. Kruse & Aaron M. Ring & Aashish Manglik & Jianxin Hu & Kelly Hu & Katrin Eitel & Harald Hübner & Els Pardon & Celine Valant & Patrick M. Sexton & Arthur Christopoulos & Christian C. Felder &, 2013. "Activation and allosteric modulation of a muscarinic acetylcholine receptor," Nature, Nature, vol. 504(7478), pages 101-106, December.
    7. Zhenhua Shao & Jie Yin & Karen Chapman & Magdalena Grzemska & Lindsay Clark & Junmei Wang & Daniel M. Rosenbaum, 2016. "High-resolution crystal structure of the human CB1 cannabinoid receptor," Nature, Nature, vol. 540(7634), pages 602-606, December.
    8. Guillaume Lebon & Tony Warne & Patricia C. Edwards & Kirstie Bennett & Christopher J. Langmead & Andrew G. W. Leslie & Christopher G. Tate, 2011. "Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation," Nature, Nature, vol. 474(7352), pages 521-525, June.
    9. Yi-Lynn Liang & Maryam Khoshouei & Alisa Glukhova & Sebastian G. B. Furness & Peishen Zhao & Lachlan Clydesdale & Cassandra Koole & Tin T. Truong & David M. Thal & Saifei Lei & Mazdak Radjainia & Rado, 2018. "Phase-plate cryo-EM structure of a biased agonist-bound human GLP-1 receptor–Gs complex," Nature, Nature, vol. 555(7694), pages 121-125, March.
    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. Hongmin Cai & Shimeng Guo & Youwei Xu & Jun Sun & Junrui Li & Zhikan Xia & Yi Jiang & Xin Xie & H. Eric Xu, 2024. "Cryo-EM structures of adenosine receptor A3AR bound to selective agonists," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    2. 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.
    3. Yosuke Toyoda & Angqi Zhu & Fang Kong & Sisi Shan & Jiawei Zhao & Nan Wang & Xiaoou Sun & Linqi Zhang & Chuangye Yan & Brian K. Kobilka & Xiangyu Liu, 2023. "Structural basis of α1A-adrenergic receptor activation and recognition by an extracellular nanobody," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    4. Kaihua Zhang & Hao Wu & Nicholas Hoppe & Aashish Manglik & Yifan Cheng, 2022. "Fusion protein strategies for cryo-EM study of G protein-coupled receptors," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    5. Elizaveta Lyapina & Egor Marin & Anastasiia Gusach & Philipp Orekhov & Andrey Gerasimov & Aleksandra Luginina & Daniil Vakhrameev & Margarita Ergasheva & Margarita Kovaleva & Georgii Khusainov & Polin, 2022. "Structural basis for receptor selectivity and inverse agonism in S1P5 receptors," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    6. Deyun Qiu & Jinxin V. Pei & James E. O. Rosling & Vandana Thathy & Dongdi Li & Yi Xue & John D. Tanner & Jocelyn Sietsma Penington & Yi Tong Vincent Aw & Jessica Yi Han Aw & Guoyue Xu & Abhai K. Tripa, 2022. "A G358S mutation in the Plasmodium falciparum Na+ pump PfATP4 confers clinically-relevant resistance to cipargamin," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    7. Shuo-Shuo Liu & Tian-Xia Jiang & Fan Bu & Ji-Lan Zhao & Guang-Fei Wang & Guo-Heng Yang & Jie-Yan Kong & Yun-Fan Qie & Pei Wen & Li-Bin Fan & Ning-Ning Li & Ning Gao & Xiao-Bo Qiu, 2024. "Molecular mechanisms underlying the BIRC6-mediated regulation of apoptosis and autophagy," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    8. Xiaoke Yang & Mingqi Zhu & Xue Lu & Yuxin Wang & Junyu Xiao, 2024. "Architecture and activation of human muscle phosphorylase kinase," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Kristy Rochon & Brianna L. Bauer & Nathaniel A. Roethler & Yuli Buckley & Chih-Chia Su & Wei Huang & Rajesh Ramachandran & Maria S. K. Stoll & Edward W. Yu & Derek J. Taylor & Jason A. Mears, 2024. "Structural basis for regulated assembly of the mitochondrial fission GTPase Drp1," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    10. Fan Lu & Liang Zhu & Thomas Bromberger & Jun Yang & Qiannan Yang & Jianmin Liu & Edward F. Plow & Markus Moser & Jun Qin, 2022. "Mechanism of integrin activation by talin and its cooperation with kindlin," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    11. Martin F. Peter & Christian Gebhardt & Rebecca Mächtel & Gabriel G. Moya Muñoz & Janin Glaenzer & Alessandra Narducci & Gavin H. Thomas & Thorben Cordes & Gregor Hagelueken, 2022. "Cross-validation of distance measurements in proteins by PELDOR/DEER and single-molecule FRET," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    12. Jutta Diessl & Jens Berndtsson & Filomena Broeskamp & Lukas Habernig & Verena Kohler & Carmela Vazquez-Calvo & Arpita Nandy & Carlotta Peselj & Sofia Drobysheva & Ludovic Pelosi & F.-Nora Vögtle & Fab, 2022. "Manganese-driven CoQ deficiency," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    13. Alexander Kroll & Sahasra Ranjan & Martin K. M. Engqvist & Martin J. Lercher, 2023. "A general model to predict small molecule substrates of enzymes based on machine and deep learning," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    14. Lisa-Marie Appel & Vedran Franke & Johannes Benedum & Irina Grishkovskaya & Xué Strobl & Anton Polyansky & Gregor Ammann & Sebastian Platzer & Andrea Neudolt & Anna Wunder & Lena Walch & Stefanie Kais, 2023. "The SPOC domain is a phosphoserine binding module that bridges transcription machinery with co- and post-transcriptional regulators," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    15. Maciej K. Kocylowski & Hande Aypek & Wolfgang Bildl & Martin Helmstädter & Philipp Trachte & Bernhard Dumoulin & Sina Wittösch & Lukas Kühne & Ute Aukschun & Carolin Teetzen & Oliver Kretz & Botond Ga, 2022. "A slit-diaphragm-associated protein network for dynamic control of renal filtration," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    16. Michael A. Longo & Sunetra Roy & Yue Chen & Karl-Heinz Tomaszowski & Andrew S. Arvai & Jordan T. Pepper & Rebecca A. Boisvert & Selvi Kunnimalaiyaan & Caezanne Keshvani & David Schild & Albino Bacolla, 2023. "RAD51C-XRCC3 structure and cancer patient mutations define DNA replication roles," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    17. Zachary C. Drake & Justin T. Seffernick & Steffen Lindert, 2022. "Protein complex prediction using Rosetta, AlphaFold, and mass spectrometry covalent labeling," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    18. Leonardo Betancurt-Anzola & Markel Martínez-Carranza & Marc Delarue & Kelly M. Zatopek & Andrew F. Gardner & Ludovic Sauguet, 2023. "Molecular basis for proofreading by the unique exonuclease domain of Family-D DNA polymerases," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    19. Karin Vogel & Tobias Bläske & Marie-Kristin Nagel & Christoph Globisch & Shane Maguire & Lorenz Mattes & Christian Gude & Michael Kovermann & Karin Hauser & Christine Peter & Erika Isono, 2022. "Lipid-mediated activation of plasma membrane-localized deubiquitylating enzymes modulate endosomal trafficking," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    20. Robin Anger & Laetitia Pieulle & Meriam Shahin & Odile Valette & Hugo Guenno & Artemis Kosta & Vladimir Pelicic & Rémi Fronzes, 2023. "Structure of a heteropolymeric type 4 pilus from a monoderm bacterium," Nature Communications, Nature, vol. 14(1), pages 1-11, 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:13:y:2022:i:1:d:10.1038_s41467-022-34696-6. 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.