Molecular basis for selective activation of DREADD-based chemogenetics

Shicheng Zhang, Ryan H. Gumpper, Xi-Ping Huang, Yongfeng Liu, Brian E. Krumm, Can Cao, Jonathan F. Fay () and Bryan L. Roth ()
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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
Yongfeng Liu: 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

Nature, 2022, vol. 612, issue 7939, 354-362

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41586-022-05489-0

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