8EA0

CryoEM structure of miniGq-coupled hM3R in complex with iperoxo (local refinement)

Summary for 8EA0

• Entry DOI: 10.2210/pdb8ea0/pdb
• EMDB information: 27970
• Descriptor: Muscarinic acetylcholine receptor M3, 4-(4,5-dihydro-1,2-oxazol-3-yloxy)-N,N,N-trimethylbut-2-yn-1-aminium, CHOLESTEROL HEMISUCCINATE (3 entities in total)
• Functional Keywords: gpcr, ixo, active state, membrane protein, hm3r, iperoxo
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 63650.60

Authors

Zhang, S.,Fay, J.F.,Roth, B.L. (deposition date: 2022-08-27, release date: 2022-11-30, Last modification date: 2025-05-21)

Primary citation

Zhang, S.,Gumpper, R.H.,Huang, X.P.,Liu, Y.,Krumm, B.E.,Cao, C.,Fay, J.F.,Roth, B.L.
Molecular basis for selective activation of DREADD-based chemogenetics.
Nature, 612:354-362, 2022

PubMed Abstract: Designer receptors exclusively activated by designer drugs (DREADDs) represent a powerful chemogenetic technology for the remote control of neuronal activity and cellular signalling. The muscarinic receptor-based DREADDs are the most widely used chemogenetic tools in neuroscience research. The G-coupled DREADD (hM3Dq) is used to enhance neuronal activity, whereas the G-coupled DREADD (hM4Di) is utilized to inhibit neuronal activity. Here we report four DREADD-related cryogenic electron microscopy high-resolution structures: a hM3Dq-miniG complex and a hM4Di-miniG complex bound to deschloroclozapine; a hM3Dq-miniG complex bound to clozapine-N-oxide; and a hM3R-miniG 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.

PubMed: 36450989
DOI: 10.1038/s41586-022-05489-0

Experimental method

ELECTRON MICROSCOPY (2.56 Å)