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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.
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    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.

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