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Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design

Author

Listed:
  • Shaoyong Lu

    (Ningxia Medical University
    Shanghai Jiao Tong University, School of Medicine)

  • Xinheng He

    (Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Zhao Yang

    (School of Medicine, Shandong University)

  • Zongtao Chai

    (Eastern Hepatobiliary Surgery Hospital, Second Military Medical University)

  • Shuhua Zhou

    (School of Medicine, Shandong University)

  • Junyan Wang

    (School of Medicine, Shandong University)

  • Ashfaq Ur Rehman

    (Shanghai Jiao Tong University, School of Medicine)

  • Duan Ni

    (Shanghai Jiao Tong University, School of Medicine)

  • Jun Pu

    (Renji Hospital, Shanghai Jiao Tong University, School of Medicine)

  • Jinpeng Sun

    (School of Medicine, Shandong University)

  • Jian Zhang

    (Ningxia Medical University
    Shanghai Jiao Tong University, School of Medicine
    Zhengzhou University)

Abstract

G protein-coupled receptors (GPCRs) are the most common proteins targeted by approved drugs. A complete mechanistic elucidation of large-scale conformational transitions underlying the activation mechanisms of GPCRs is of critical importance for therapeutic drug development. Here, we apply a combined computational and experimental framework integrating extensive molecular dynamics simulations, Markov state models, site-directed mutagenesis, and conformational biosensors to investigate the conformational landscape of the angiotensin II (AngII) type 1 receptor (AT1 receptor) — a prototypical class A GPCR—activation. Our findings suggest a synergistic transition mechanism for AT1 receptor activation. A key intermediate state is identified in the activation pathway, which possesses a cryptic binding site within the intracellular region of the receptor. Mutation of this cryptic site prevents activation of the downstream G protein signaling and β-arrestin-mediated pathways by the endogenous AngII octapeptide agonist, suggesting an allosteric regulatory mechanism. Together, these findings provide a deeper understanding of AT1 receptor activation at an atomic level and suggest avenues for the design of allosteric AT1 receptor modulators with a broad range of applications in GPCR biology, biophysics, and medicinal chemistry.

Suggested Citation

  • Shaoyong Lu & Xinheng He & Zhao Yang & Zongtao Chai & Shuhua Zhou & Junyan Wang & Ashfaq Ur Rehman & Duan Ni & Jun Pu & Jinpeng Sun & Jian Zhang, 2021. "Activation pathway of a G protein-coupled receptor uncovers conformational intermediates as targets for allosteric drug design," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25020-9
    DOI: 10.1038/s41467-021-25020-9
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    Cited by:

    1. 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.
    2. Xinheng He & Lifen Zhao & Yinping Tian & Rui Li & Qinyu Chu & Zhiyong Gu & Mingyue Zheng & Yusong Wang & Shaoning Li & Hualiang Jiang & Yi Jiang & Liuqing Wen & Dingyan Wang & Xi Cheng, 2024. "Highly accurate carbohydrate-binding site prediction with DeepGlycanSite," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    3. Janik B. Hedderich & Margherita Persechino & Katharina Becker & Franziska M. Heydenreich & Torben Gutermuth & Michel Bouvier & Moritz Bünemann & Peter Kolb, 2022. "The pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Federica Maschietto & Uriel N. Morzan & Florentina Tofoleanu & Aria Gheeraert & Apala Chaudhuri & Gregory W. Kyro & Peter Nekrasov & Bernard Brooks & J. Patrick Loria & Ivan Rivalta & Victor S. Batist, 2023. "Turning up the heat mimics allosteric signaling in imidazole-glycerol phosphate synthase," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Yusong Wang & Tong Wang & Shaoning Li & Xinheng He & Mingyu Li & Zun Wang & Nanning Zheng & Bin Shao & Tie-Yan Liu, 2024. "Enhancing geometric representations for molecules with equivariant vector-scalar interactive message passing," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    6. Mingyu Li & Xiaobing Lan & Xinchao Shi & Chunhao Zhu & Xun Lu & Jun Pu & Shaoyong Lu & Jian Zhang, 2024. "Delineating the stepwise millisecond allosteric activation mechanism of the class C GPCR dimer mGlu5," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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