8ea0

From Proteopedia

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

Structural highlights

8ea0 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.56Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ACM3_HUMAN Defects in CHRM3 are the cause of Eagle-Barrett syndrome (EGBRS) [MIM:100100. EGBRS is a syndrome characterized by thin abdominal musculature with overlying lax skin, cryptorchism, megacystis with disorganized detrusor muscle, and urinary tract abnormalities.^[1]

Function

ACM3_HUMAN The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is Pi turnover.

Publication Abstract from PubMed

Designer receptors exclusively activated by designer drugs (DREADDs) represent a powerful chemogenetic technology for the remote control of neuronal activity and cellular signalling(1-4). The muscarinic receptor-based DREADDs are the most widely used chemogenetic tools in neuroscience research. The G(q)-coupled DREADD (hM3Dq) is used to enhance neuronal activity, whereas the G(i/o)-coupled DREADD (hM4Di) is utilized to inhibit neuronal activity(5). Here we report four DREADD-related cryogenic electron microscopy high-resolution structures: a hM3Dq-miniG(q) complex and a hM4Di-miniG(o) complex bound to deschloroclozapine; a hM3Dq-miniG(q) complex bound to clozapine-N-oxide; and a hM3R-miniG(q) 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.

Molecular basis for selective activation of DREADD-based chemogenetics.,Zhang S, Gumpper RH, Huang XP, Liu Y, Krumm BE, Cao C, Fay JF, Roth BL Nature. 2022 Dec;612(7939):354-362. doi: 10.1038/s41586-022-05489-0. Epub 2022 , Nov 30. PMID:36450989^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Weber S, Thiele H, Mir S, Toliat MR, Sozeri B, Reutter H, Draaken M, Ludwig M, Altmuller J, Frommolt P, Stuart HM, Ranjzad P, Hanley NA, Jennings R, Newman WG, Wilcox DT, Thiel U, Schlingmann KP, Beetz R, Hoyer PF, Konrad M, Schaefer F, Nurnberg P, Woolf AS. Muscarinic Acetylcholine Receptor M3 Mutation Causes Urinary Bladder Disease and a Prune-Belly-like Syndrome. Am J Hum Genet. 2011 Nov 11;89(5):668-74. doi: 10.1016/j.ajhg.2011.10.007. PMID:22077972 doi:10.1016/j.ajhg.2011.10.007
↑ Zhang S, Gumpper RH, Huang XP, Liu Y, Krumm BE, Cao C, Fay JF, Roth BL. Molecular basis for selective activation of DREADD-based chemogenetics. Nature. 2022 Dec;612(7939):354-362. PMID:36450989 doi:10.1038/s41586-022-05489-0