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Structure paper

TitleThe unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands.
Journal, issue, pagesNat Commun, Vol. 13, Issue 1, Page 2855, Year 2022
Publish dateMay 23, 2022
AuthorsJingjing Wang / Meng Wu / Zhangcheng Chen / Lijie Wu / Tian Wang / Dongmei Cao / Huan Wang / Shenhui Liu / Yueming Xu / Fei Li / Junlin Liu / Na Chen / Suwen Zhao / Jianjun Cheng / Sheng Wang / Tian Hua /
PubMed AbstractMuscarinic acetylcholine receptors (mAChRs) respond to the neurotransmitter acetylcholine and play important roles in human nervous system. Muscarinic receptor 4 (M4R) is a promising drug target for ...Muscarinic acetylcholine receptors (mAChRs) respond to the neurotransmitter acetylcholine and play important roles in human nervous system. Muscarinic receptor 4 (M4R) is a promising drug target for treating neurological and mental disorders, such as Alzheimer's disease and schizophrenia. However, the lack of understanding on M4R's activation by subtype selective agonists hinders its therapeutic applications. Here, we report the structural characterization of M4R selective allosteric agonist, compound-110, as well as agonist iperoxo and positive allosteric modulator LY2119620. Our cryo-electron microscopy structures of compound-110, iperoxo or iperoxo-LY2119620 bound M4R-G complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-G structure validates the cooperativity between iperoxo and LY2119620 on M4R. Through the comparative structural and pharmacological analysis, compound-110 mostly occupies the allosteric binding pocket with vertical binding pose. Such a binding and activation mode facilitates its allostersic selectivity and agonist profile. In addition, in our schizophrenia-mimic mouse model study, compound-110 shows antipsychotic activity with low extrapyramidal side effects. Thus, this study provides structural insights to develop next-generation antipsychotic drugs selectively targeting on mAChRs subtypes.
External linksNat Commun / PubMed:35606397 / PubMed Central
MethodsEM (single particle)
Resolution3.4 - 3.6 Å
Structure data

31738

7v68

EMDB-31738, PDB-7v68:
An Agonist and PAM-bound Class A GPCR with Gi protein complex structure
Method: EM (single particle) / Resolution: 3.4 Å

31739

7v69

EMDB-31739, PDB-7v69:
Cryo-EM structure of a class A GPCR-G protein complex
Method: EM (single particle) / Resolution: 3.4 Å

31740

7v6a

EMDB-31740, PDB-7v6a:
Cry-EM structure of M4-c110-G protein complex
Method: EM (single particle) / Resolution: 3.6 Å

Chemicals

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

ChemComp-2CU:
3-amino-5-chloro-N-cyclopropyl-4-methyl-6-[2-(4-methylpiperazin-1-yl)-2-oxoethoxy]thieno[2,3-b]pyridine-2-carboxamide

ChemComp-5XI:
methyl 4-[4-(3-methyl-2-oxidanylidene-benzimidazol-1-yl)piperidin-1-yl]piperidine-1-carboxylate

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / M4R-Gi complex / Complex

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