Allostery of atypical modulators at oligomeric G protein-coupled receptors

Rabindra V. Shivnaraine, Brendan Kelly, Gwendolynne Elmslie, Xi Ping Huang, Yue John Dong, Margaret Seidenberg, James W. Wells, John Ellis

Research output: Contribution to journalArticlepeer-review

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 monomers and oligomers of wild-type and mutant M2 receptors. Tacrine is not atypical at monomers, which indicates that its atypical effects are a property of the receptor in its oligomeric state. These results illustrate that oligomerization of the M2 receptor has functional consequences.

Original languageEnglish (US)
Article number9265
JournalScientific reports
Volume11
Issue number1
DOIs
StatePublished - Dec 2021

All Science Journal Classification (ASJC) codes

  • General

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