The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands.

ABSTRACT: 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_i complex reveal their different interaction modes and activation mechanisms of M4R, and the M4R-ip-LY-G

SUBMITTER: Wang J 

PROVIDER: S-EPMC9126879 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature