Allostery of atypical modulators at oligomeric G protein-coupled receptors

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

doi:10.1038/s41598-021-88399-x

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.

Highlights

Many G protein-coupled receptors (GPCRs) are therapeutic targets, with most drugs acting at the orthosteric site
G protein-coupled receptors (GPCRs) regulate cellular signaling through conformational changes and effects on protein–protein interactions[1]
The activated GPCR couples to intracellular proteins in a sequence that begins with G proteins, followed in turn by G Protein-coupled Receptor Kinases (GRKs) and A rrestins[3]

Summary

Introduction

Many G protein-coupled receptors (GPCRs) are therapeutic targets, with most drugs acting at the orthosteric site. The activated GPCR couples to intracellular proteins in a sequence that begins with G proteins, followed in turn by G Protein-coupled Receptor Kinases (GRKs) and A rrestins[3] This canonical process is consistent with much biophysical data, and it has informed much activity in the realm of drug discovery[4]. GPCRs are known to be multi-conformational and to act directly on different effectors depending upon the conformation favored by the agonist, an effect known as biased signaling[3] They are known to occur as oligomers, allowing for protein–protein interactions between neighboring receptors as well as between the receptor and other proteins in the signaling pathway[5,6,7].

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Conclusion