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Molecular basis for selective activation of DREADD-based chemogenetics

Author

Listed:
  • Shicheng Zhang

    (University of North Carolina at Chapel Hill)

  • Ryan H. Gumpper

    (University of North Carolina at Chapel Hill)

  • Xi-Ping Huang

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Yongfeng Liu

    (University of North Carolina at Chapel Hill
    University of North Carolina at Chapel Hill)

  • Brian E. Krumm

    (University of North Carolina at Chapel Hill)

  • Can Cao

    (University of North Carolina at Chapel Hill)

  • Jonathan F. Fay

    (University of Maryland School of Medicine)

  • Bryan L. Roth

    (University of North Carolina at Chapel Hill)

Abstract

Designer receptors exclusively activated by designer drugs (DREADDs) represent a powerful chemogenetic technology for the remote control of neuronal activity and cellular signalling1–4. The muscarinic receptor-based DREADDs are the most widely used chemogenetic tools in neuroscience research. The Gq-coupled DREADD (hM3Dq) is used to enhance neuronal activity, whereas the Gi/o-coupled DREADD (hM4Di) is utilized to inhibit neuronal activity5. Here we report four DREADD-related cryogenic electron microscopy high-resolution structures: a hM3Dq–miniGq complex and a hM4Di–miniGo complex bound to deschloroclozapine; a hM3Dq–miniGq complex bound to clozapine-N-oxide; and a hM3R–miniGq complex bound to iperoxo. Complemented with mutagenesis, functional and computational simulation data, our structures reveal key details of the recognition of DREADD chemogenetic actuators and the molecular basis for activation. These findings should accelerate the structure-guided discovery of next-generation chemogenetic tools.

Suggested Citation

  • Shicheng Zhang & Ryan H. Gumpper & Xi-Ping Huang & Yongfeng Liu & Brian E. Krumm & Can Cao & Jonathan F. Fay & Bryan L. Roth, 2022. "Molecular basis for selective activation of DREADD-based chemogenetics," Nature, Nature, vol. 612(7939), pages 354-362, December.
    • Handle: RePEc:nat:nature:v:612:y:2022:i:7939:d:10.1038_s41586-022-05489-0
    DOI: 10.1038/s41586-022-05489-0
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    Cited by:

    1. Liu Liu & Kimberley EI & Diptadip Dattaroy & Luiz F. Barella & Yinghong Cui & Sarah M. Gray & Carla Guedikian & Min Chen & Lee S. Weinstein & Emily Knuth & Erli Jin & Matthew J. Merrins & Jeffrey Roma, 2024. "Intra-islet α-cell Gs signaling promotes glucagon release," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Wessel A. C. Burger & Vi Pham & Ziva Vuckovic & Alexander S. Powers & Jesse I. Mobbs & Yianni Laloudakis & Alisa Glukhova & Denise Wootten & Andrew B. Tobin & Patrick M. Sexton & Steven M. Paul & Chri, 2023. "Xanomeline displays concomitant orthosteric and allosteric binding modes at the M4 mAChR," Nature Communications, Nature, vol. 14(1), pages 1-11, December.

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