IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-36971-6.html
   My bibliography  Save this article

Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery

Author

Listed:
  • Xudong Wang

    (University of South Florida)

  • Chris Neale

    (Los Alamos National Laboratory)

  • Soo-Kyung Kim

    (California Institute of Technology)

  • William A. Goddard

    (California Institute of Technology)

  • Libin Ye

    (University of South Florida
    H. Lee Moffitt Cancer Center & Research Institute)

Abstract

Understanding the roles of intermediate states in signaling is pivotal to unraveling the activation processes of G protein-coupled receptors (GPCRs). However, the field is still struggling to define these conformational states with sufficient resolution to study their individual functions. Here, we demonstrate the feasibility of enriching the populations of discrete states via conformation-biased mutants. These mutants adopt distinct distributions among five states that lie along the activation pathway of adenosine A2A receptor (A2AR), a class A GPCR. Our study reveals a structurally conserved cation-π lock between transmembrane helix VI (TM6) and Helix8 that regulates cytoplasmic cavity opening as a “gatekeeper” for G protein penetration. A GPCR activation process based on the well-discerned conformational states is thus proposed, allosterically micro-modulated by the cation-π lock and a previously well-defined ionic interaction between TM3 and TM6. Intermediate-state-trapped mutants will also provide useful information in relation to receptor-G protein signal transduction.

Suggested Citation

  • Xudong Wang & Chris Neale & Soo-Kyung Kim & William A. Goddard & Libin Ye, 2023. "Intermediate-state-trapped mutants pinpoint G protein-coupled receptor conformational allostery," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36971-6
    DOI: 10.1038/s41467-023-36971-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-36971-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-023-36971-6?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. Sarah L. Lovelock & Rebecca Crawshaw & Sophie Basler & Colin Levy & David Baker & Donald Hilvert & Anthony P. Green, 2022. "The road to fully programmable protein catalysis," Nature, Nature, vol. 606(7912), pages 49-58, June.
    2. Yi-Lynn Liang & Maryam Khoshouei & Mazdak Radjainia & Yan Zhang & Alisa Glukhova & Jeffrey Tarrasch & David M. Thal & Sebastian G. B. Furness & George Christopoulos & Thomas Coudrat & Radostin Danev &, 2017. "Phase-plate cryo-EM structure of a class B GPCR–G-protein complex," Nature, Nature, vol. 546(7656), pages 118-123, June.
    3. Libin Ye & Chris Neale & Adnan Sljoka & Brent Lyda & Dmitry Pichugin & Nobuyuki Tsuchimura & Sacha T. Larda & Régis Pomès & Angel E. García & Oliver P. Ernst & Roger K. Sunahara & R. Scott Prosser, 2018. "Mechanistic insights into allosteric regulation of the A2A adenosine G protein-coupled receptor by physiological cations," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    4. 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.
    5. Yan Zhang & Bingfa Sun & Dan Feng & Hongli Hu & Matthew Chu & Qianhui Qu & Jeffrey T. Tarrasch & Shane Li & Tong Sun Kobilka & Brian K. Kobilka & Georgios Skiniotis, 2017. "Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein," Nature, Nature, vol. 546(7657), pages 248-253, June.
    6. Libin Ye & Ned Van Eps & Marco Zimmer & Oliver P. Ernst & R. Scott Prosser, 2016. "Activation of the A2A adenosine G-protein-coupled receptor by conformational selection," Nature, Nature, vol. 533(7602), pages 265-268, May.
    7. 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)

    Citations

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


    Cited by:

    1. Maxine Bi & Xudong Wang & Jinan Wang & Jun Xu & Wenkai Sun & Victor Ayo Adediwura & Yinglong Miao & Yifan Cheng & Libin Ye, 2025. "Structure and function of a near fully-activated intermediate GPCR-Gαβγ complex," Nature Communications, Nature, vol. 16(1), pages 1-14, 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. Yong-Seok Kim & Jun-Hee Yeon & Woori Ko & Byung-Chang Suh, 2023. "Two-step structural changes in M3 muscarinic receptor activation rely on the coupled Gq protein cycle," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    2. Li-Hua Zhao & Jingyu Lin & Su-Yu Ji & X. Edward Zhou & Chunyou Mao & Dan-Dan Shen & Xinheng He & Peng Xiao & Jinpeng Sun & Karsten Melcher & Yan Zhang & Xiao Yu & H. Eric Xu, 2022. "Structure insights into selective coupling of G protein subtypes by a class B G protein-coupled receptor," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Maxine Bi & Xudong Wang & Jinan Wang & Jun Xu & Wenkai Sun & Victor Ayo Adediwura & Yinglong Miao & Yifan Cheng & Libin Ye, 2025. "Structure and function of a near fully-activated intermediate GPCR-Gαβγ complex," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    4. Julien Bous & Julia Kinsolving & Lukas Grätz & Magdalena M. Scharf & Jan Hendrik Voss & Berkay Selcuk & Ogün Adebali & Gunnar Schulte, 2024. "Structural basis of frizzled 7 activation and allosteric regulation," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. 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.
    6. Fenghui Zhao & Qingtong Zhou & Zhaotong Cong & Kaini Hang & Xinyu Zou & Chao Zhang & Yan Chen & Antao Dai & Anyi Liang & Qianqian Ming & Mu Wang & Li-Nan Chen & Peiyu Xu & Rulve Chang & Wenbo Feng & T, 2022. "Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. 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.
    8. Jun-Kuan Li & Ge Qu & Xu Li & Yuchen Tian & Chengsen Cui & Fa-Guang Zhang & Wuyuan Zhang & Jun-An Ma & Manfred T. Reetz & Zhoutong Sun, 2022. "Rational enzyme design for enabling biocatalytic Baldwin cyclization and asymmetric synthesis of chiral heterocycles," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    9. Kaleeckal G. Harikumar & Sarah J. Piper & Arthur Christopoulos & Denise Wootten & Patrick M. Sexton & Laurence J. Miller, 2024. "Impact of secretin receptor homo-dimerization on natural ligand binding," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    10. Andrew J. Y. Jones & Thomas H. Harman & Matthew Harris & Oliver E. Lewis & Graham Ladds & Daniel Nietlispach, 2024. "Binding kinetics drive G protein subtype selectivity at the β1-adrenergic receptor," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    11. Xueqian Peng & Linlin Yang & Zixuan Liu & Siyi Lou & Shiliu Mei & Meiling Li & Zhong Chen & Haitao Zhang, 2022. "Structural basis for recognition of antihistamine drug by human histamine receptor," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    12. Amy E. Hutton & Jake Foster & Rebecca Crawshaw & Florence J. Hardy & Linus O. Johannissen & Thomas M. Lister & Emilie F. Gérard & Zachary Birch-Price & Richard Obexer & Sam Hay & Anthony P. Green, 2024. "A non-canonical nucleophile unlocks a new mechanistic pathway in a designed enzyme," Nature Communications, Nature, vol. 15(1), pages 1-13, 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. Haoran Huang & Tao Yan & Chang Liu & Yuxiang Lu & Zhigang Wu & Xingchu Wang & Jie Wang, 2024. "Genetically encoded Nδ-vinyl histidine for the evolution of enzyme catalytic center," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    15. Thomas L. Williams & Grégory Verdon & Rhoda E. Kuc & Heather Currinn & Brian Bender & Nicolae Solcan & Oliver Schlenker & Robyn G. C. Macrae & Jason Brown & Marco Schütz & Andrei Zhukov & Sanjay Sinha, 2024. "Structural and functional determination of peptide versus small molecule ligand binding at the apelin receptor," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    16. Michael W. Martynowycz & Anna Shiriaeva & Max T. B. Clabbers & William J. Nicolas & Sara J. Weaver & Johan Hattne & Tamir Gonen, 2023. "A robust approach for MicroED sample preparation of lipidic cubic phase embedded membrane protein crystals," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    17. Thuy N. Nguyen & Christine Ingle & Samuel Thompson & Kimberly A. Reynolds, 2024. "The genetic landscape of a metabolic interaction," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    18. Robert E. Jefferson & Aurélien Oggier & Andreas Füglistaler & Nicolas Camviel & Mahdi Hijazi & Ana Rico Villarreal & Caroline Arber & Patrick Barth, 2023. "Computational design of dynamic receptor—peptide signaling complexes applied to chemotaxis," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    19. Qi Zhao & Xu-Qin Ran & Zhu-Ying Yan & Hai-Long Qian & Xiu-Ping Yan, 2025. "Histamine-modulated wettability switching in G-protein-coupled receptor inspired nanochannel for potential drug screening and biosensing," Nature Communications, Nature, vol. 16(1), pages 1-9, December.
    20. Jie Yin & Yanyong Kang & Aaron P. McGrath & Karen Chapman & Megan Sjodt & Eiji Kimura & Atsutoshi Okabe & Tatsuki Koike & Yuhei Miyanohana & Yuji Shimizu & Rameshu Rallabandi & Peng Lian & Xiaochen Ba, 2022. "Molecular mechanism of the wake-promoting agent TAK-925," Nature Communications, Nature, vol. 13(1), pages 1-12, 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_s41467-023-36971-6. 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.