The structural study of mutation-induced inactivation of human muscarinic receptor M4.

ABSTRACT: Human muscarinic receptor M4 belongs to the class A subfamily of the G-protein-coupled receptors (GPCRs). M4 has emerged as an attractive drug target for the treatment of Alzheimer's disease and schizophrenia. Recent results showed that M4-mediated cholinergic transmission is related to motor symptoms in Parkinson's disease. Selective ligand design for the five muscarinic acetylcholine receptor (mAchR) subtypes currently remains challenging owing to the high sequence and structural similarity of their orthosteric binding pockets. In order to obtain M4-selective antagonists, a new approach was tried to lock M4 into an inactive form by rationally designing an N449^7.49R mutation, which mimics the allosteric sodium binding in the conserved sodium site usually found in class A GPCRs.

SUBMITTER: Wang J 

PROVIDER: S-EPMC7055379 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature