7V68

An Agonist and PAM-bound Class A GPCR with Gi protein complex structure

Summary for 7V68

• Entry DOI: 10.2210/pdb7v68/pdb
• EMDB information: 31738 31739 31740
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2, ... (7 entities in total)
• Functional Keywords: m4r-gi complex, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 153181.17

Authors

Wang, J.J.,Wu, L.J.,Wu, M.,Hua, T.,Liu, Z.J.,Wang, T. (deposition date: 2021-08-20, release date: 2022-05-11, Last modification date: 2024-11-06)

Primary citation

Wang, J.,Wu, M.,Chen, Z.,Wu, L.,Wang, T.,Cao, D.,Wang, H.,Liu, S.,Xu, Y.,Li, F.,Liu, J.,Chen, N.,Zhao, S.,Cheng, J.,Wang, S.,Hua, T.
The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands.
Nat Commun, 13:2855-2855, 2022

PubMed 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 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.

PubMed: 35606397
DOI: 10.1038/s41467-022-30595-y

Experimental method

ELECTRON MICROSCOPY (3.4 Å)