7v68

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

spinqualitylabelsall models 7v68, resolution 3.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7v68 is a 5 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 3.4Å Ligands: 2CU, IXO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ACM4_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 inhibition of adenylate cyclase. Publication Abstract from PubMed 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(i) 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. The unconventional activation of the muscarinic acetylcholine receptor M4R by diverse ligands.,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 Nat Commun. 2022 May 23;13(1):2855. doi: 10.1038/s41467-022-30595-y. PMID:35606397 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Muscarinic acetylcholine receptor Transducin 3D structures

Proteopedia Page Contributors and Editors (what is this?)

OCA