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Structure paper

TitleMolecular basis for selective activation of DREADD-based chemogenetics.
Journal, issue, pagesNature, Vol. 612, Issue 7939, Page 354-362, Year 2022
Publish dateNov 30, 2022
AuthorsShicheng Zhang / Ryan H Gumpper / Xi-Ping Huang / Yongfeng Liu / Brian E Krumm / Can Cao / Jonathan F Fay / Bryan L Roth /
PubMed AbstractDesigner receptors exclusively activated by designer drugs (DREADDs) represent a powerful chemogenetic technology for the remote control of neuronal activity and cellular signalling. The muscarinic ...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.
External linksNature / PubMed:36450989
MethodsEM (single particle)
Resolution2.56 - 2.79 Å
Structure data

27966

8e9w

EMDB-27966, PDB-8e9w:
CryoEM structure of miniGq-coupled hM3Dq in complex with DCZ
Method: EM (single particle) / Resolution: 2.69 Å

27967

8e9x

EMDB-27967, PDB-8e9x:
CryoEM structure of miniGo-coupled hM4Di in complex with DCZ
Method: EM (single particle) / Resolution: 2.7 Å

27968

8e9y

EMDB-27968, PDB-8e9y:
CryoEM structure of miniGq-coupled hM3Dq in complex with CNO
Method: EM (single particle) / Resolution: 2.79 Å

27969

8e9z

EMDB-27969, PDB-8e9z:
CryoEM structure of miniGq-coupled hM3R in complex with Iperoxo
Method: EM (single particle) / Resolution: 2.69 Å

27970

8ea0

EMDB-27970, PDB-8ea0:
CryoEM structure of miniGq-coupled hM3R in complex with iperoxo (local refinement)
Method: EM (single particle) / Resolution: 2.56 Å

Chemicals

ChemComp-WEC:
11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine

ChemComp-WE9:
8-chloro-11-(4-methyl-4-oxo-4lambda~5~-piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine

ChemComp-IXO:
4-(4,5-dihydro-1,2-oxazol-3-yloxy)-N,N,N-trimethylbut-2-yn-1-aminium

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / GPCR / Deschloroclozapine / DCZ / active state / hM3Dq / hM3R / DREADD / hM4Di / CNO / IXO / Iperoxo

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