Allostery of atypical modulators at oligomeric G protein-coupled receptors.

ABSTRACT: Many G protein-coupled receptors (GPCRs) are therapeutic targets, with most drugs acting at the orthosteric site. Some GPCRs also possess allosteric sites, which have become a focus of drug discovery. In the M₂ muscarinic receptor, allosteric modulators regulate the binding and functional effects of orthosteric ligands through a mix of conformational changes, steric hindrance and electrostatic repulsion transmitted within and between the constituent protomers of an oligomer. Tacrine has been called an atypical modulator because it exhibits positive cooperativity, as revealed by Hill coefficients greater than 1 in its negative allosteric effect on binding and response. Radioligand binding and molecular dynamics simulations were used to probe the mechanism of that modulation in mo

SUBMITTER: Shivnaraine RV 

PROVIDER: S-EPMC8085029 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature