IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-38894-8.html
   My bibliography  Save this article

Stabilization of pre-existing neurotensin receptor conformational states by β-arrestin-1 and the biased allosteric modulator ML314

Author

Listed:
  • Fabian Bumbak

    (Indiana University
    Monash University)

  • James B. Bower

    (Indiana University)

  • Skylar C. Zemmer

    (Indiana University)

  • Asuka Inoue

    (Tohoku University)

  • Miquel Pons

    (Universitat de Barcelona (UB))

  • Juan Carlos Paniagua

    (Universitat de Barcelona (UB))

  • Fei Yan

    (University of Melbourne)

  • James Ford

    (Indiana University)

  • Hongwei Wu

    (Indiana University
    School of Chemistry & Biochemistry, Georgia Institute of Technology)

  • Scott A. Robson

    (Indiana University)

  • Ross A. D. Bathgate

    (The University of Melbourne)

  • Daniel J. Scott

    (The University of Melbourne)

  • Paul R. Gooley

    (University of Melbourne)

  • Joshua J. Ziarek

    (Indiana University)

Abstract

The neurotensin receptor 1 (NTS1) is a G protein-coupled receptor (GPCR) with promise as a drug target for the treatment of pain, schizophrenia, obesity, addiction, and various cancers. A detailed picture of the NTS1 structural landscape has been established by X-ray crystallography and cryo-EM and yet, the molecular determinants for why a receptor couples to G protein versus arrestin transducers remain poorly defined. We used 13CεH3-methionine NMR spectroscopy to show that binding of phosphatidylinositol-4,5-bisphosphate (PIP2) to the receptor’s intracellular surface allosterically tunes the timescale of motions at the orthosteric pocket and conserved activation motifs – without dramatically altering the structural ensemble. β-arrestin-1 further remodels the receptor ensemble by reducing conformational exchange kinetics for a subset of resonances, whereas G protein coupling has little to no effect on exchange rates. A β-arrestin biased allosteric modulator transforms the NTS1:G protein complex into a concatenation of substates, without triggering transducer dissociation, suggesting that it may function by stabilizing signaling incompetent G protein conformations such as the non-canonical state. Together, our work demonstrates the importance of kinetic information to a complete picture of the GPCR activation landscape.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38894-8
    DOI: 10.1038/s41467-023-38894-8
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-38894-8
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-38894-8?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. Hsin-Yung Yen & Kin Kuan Hoi & Idlir Liko & George Hedger & Michael R. Horrell & Wanling Song & Di Wu & Philipp Heine & Tony Warne & Yang Lee & Byron Carpenter & Andreas Plückthun & Christopher G. Tat, 2018. "PtdIns(4,5)P2 stabilizes active states of GPCRs and enhances selectivity of G-protein coupling," Nature, Nature, vol. 559(7714), pages 423-427, July.
    2. Yutaro Shiraishi & Mei Natsume & Yutaka Kofuku & Shunsuke Imai & Kunio Nakata & Toshimi Mizukoshi & Takumi Ueda & Hideo Iwaï & Ichio Shimada, 2018. "Phosphorylation-induced conformation of β2-adrenoceptor related to arrestin recruitment revealed by NMR," Nature Communications, Nature, vol. 9(1), pages 1-10, December.
    3. Weijiao Huang & Matthieu Masureel & Qianhui Qu & John Janetzko & Asuka Inoue & Hideaki E. Kato & Michael J. Robertson & Khanh C. Nguyen & Jeffrey S. Glenn & Georgios Skiniotis & Brian K. Kobilka, 2020. "Structure of the neurotensin receptor 1 in complex with β-arrestin 1," Nature, Nature, vol. 579(7798), pages 303-308, March.
    4. Kathryn M. Hart & Chris M. W. Ho & Supratik Dutta & Michael L. Gross & Gregory R. Bowman, 2016. "Modelling proteins’ hidden conformations to predict antibiotic resistance," Nature Communications, Nature, vol. 7(1), pages 1-10, December.
    5. 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.
    6. Yutaro Shiraishi & Yutaka Kofuku & Takumi Ueda & Shubhi Pandey & Hemlata Dwivedi-Agnihotri & Arun K. Shukla & Ichio Shimada, 2021. "Biphasic activation of β-arrestin 1 upon interaction with a GPCR revealed by methyl-TROSY NMR," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    7. 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.
    8. F. Pontiggia & D.V. Pachov & M.W. Clarkson & J. Villali & M.F. Hagan & V.S. Pande & D. Kern, 2015. "Free energy landscape of activation in a signalling protein at atomic resolution," Nature Communications, Nature, vol. 6(1), pages 1-14, November.
    9. Marjorie Damian & Maxime Louet & Antoniel Augusto Severo Gomes & Céline M’Kadmi & Séverine Denoyelle & Sonia Cantel & Sophie Mary & Paulo M. Bisch & Jean-Alain Fehrentz & Laurent J. Catoire & Nicolas , 2021. "Allosteric modulation of ghrelin receptor signaling by lipids," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    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. Junke Liu & Hengmin Tang & Chanjuan Xu & Shengnan Zhou & Xunying Zhu & Yuanyuan Li & Laurent Prézeau & Tao Xu & Jean-Philippe Pin & Philippe Rondard & Wei Ji & Jianfeng Liu, 2022. "Biased signaling due to oligomerization of the G protein-coupled platelet-activating factor receptor," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. T. Bertie Ansell & Wanling Song & Claire E. Coupland & Loic Carrique & Robin A. Corey & Anna L. Duncan & C. Keith Cassidy & Maxwell M. G. Geurts & Tim Rasmussen & Andrew B. Ward & Christian Siebold & , 2023. "LipIDens: simulation assisted interpretation of lipid densities in cryo-EM structures of membrane proteins," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. 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.
    4. Matthew A. Cruz & Thomas E. Frederick & Upasana L. Mallimadugula & Sukrit Singh & Neha Vithani & Maxwell I. Zimmerman & Justin R. Porter & Katelyn E. Moeder & Gaya K. Amarasinghe & Gregory R. Bowman, 2022. "A cryptic pocket in Ebola VP35 allosterically controls RNA binding," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    5. Alexandre Pozza & François Giraud & Quentin Cece & Marina Casiraghi & Elodie Point & Marjorie Damian & Christel Le Bon & Karine Moncoq & Jean-Louis Banères & Ewen Lescop & Laurent J. Catoire, 2022. "Exploration of the dynamic interplay between lipids and membrane proteins by hydrostatic pressure," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    6. 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.
    7. 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.
    8. Di Wu & Renhong Yan & Siyuan Song & Andrew K. Swansiger & Yaning Li & James S. Prell & Qiang Zhou & Carol V. Robinson, 2024. "The complete assembly of human LAT1-4F2hc complex provides insights into its regulation, function and localisation," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    9. Trayder Thomas & Benoît Roux, 2021. "Tyrosine kinases: complex molecular systems challenging computational methodologies," The European Physical Journal B: Condensed Matter and Complex Systems, Springer;EDP Sciences, vol. 94(10), pages 1-13, October.
    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. Mitchell Brüderlin & Raphael Böhm & Firas Fadel & Sebastian Hiller & Tilman Schirmer & Badri N. Dubey, 2023. "Structural features discriminating hybrid histidine kinase Rec domains from response regulator homologs," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    13. Amal El Daibani & Joseph M. Paggi & Kuglae Kim & Yianni D. Laloudakis & Petr Popov & Sarah M. Bernhard & Brian E. Krumm & Reid H. J. Olsen & Jeffrey Diberto & F. Ivy Carroll & Vsevolod Katritch & Bern, 2023. "Molecular mechanism of biased signaling at the kappa opioid receptor," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    14. 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.
    15. Raphael Reher & Allegra T. Aron & Pavla Fajtová & Paolo Stincone & Berenike Wagner & Alicia I. Pérez-Lorente & Chenxi Liu & Ido Y. Ben Shalom & Wout Bittremieux & Mingxun Wang & Kyowon Jeong & Marie L, 2022. "Native metabolomics identifies the rivulariapeptolide family of protease inhibitors," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    16. Jie Heng & Yunfei Hu & Guillermo Pérez-Hernández & Asuka Inoue & Jiawei Zhao & Xiuyan Ma & Xiaoou Sun & Kouki Kawakami & Tatsuya Ikuta & Jienv Ding & Yujie Yang & Lujia Zhang & Sijia Peng & Xiaogang N, 2023. "Function and dynamics of the intrinsically disordered carboxyl terminus of β2 adrenergic receptor," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    17. Yutaro Shiraishi & Yutaka Kofuku & Takumi Ueda & Shubhi Pandey & Hemlata Dwivedi-Agnihotri & Arun K. Shukla & Ichio Shimada, 2021. "Biphasic activation of β-arrestin 1 upon interaction with a GPCR revealed by methyl-TROSY NMR," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
    18. 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.
    19. Aslihan Shenol & Ricardo Tenente & Michael Lückmann & Thomas M. Frimurer & Thue W. Schwartz, 2024. "Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode," Nature Communications, Nature, vol. 15(1), pages 1-10, December.
    20. 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.

    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_s41467-023-38894-8. 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.