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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
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    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    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. 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.
    6. 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.
    7. 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.
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