Correlated Motions of Conserved Polar Motifs Lay out a Plausible Mechanism of G Protein-Coupled Receptor Activation.

Argha Mitra,Attila Borics,Márton Richárd Szabó,Arijit Sarkar

doi:10.3390/biom11050670

Argha Mitra, Attila Borics + Show 2 more

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https://doi.org/10.3390/biom11050670

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Abstract

Recent advancements in the field of experimental structural biology have provided high-resolution structures of active and inactive state G protein-coupled receptors (GPCRs), a highly important pharmaceutical target family, but the process of transition between these states is poorly understood. According to the current theory, GPCRs exist in structurally distinct, dynamically interconverting functional states of which populations are shifted upon binding of ligands and intracellular signaling proteins. However, explanation of the activation mechanism, on an entirely structural basis, gets complicated when multiple activation pathways and active receptor states are considered. Our unbiased, atomistic molecular dynamics simulations of the μ opioid receptor (MOP) revealed that transmission of external stimulus to the intracellular surface of the receptor is accompanied by subtle, concerted movements of highly conserved polar amino acid side chains along the 7th transmembrane helix. This may entail the rearrangement of polar species and the shift of macroscopic polarization in the transmembrane domain, triggered by agonist binding. Based on our observations and numerous independent indications, we suggest amending the widely accepted theory that the initiation event of GPCR activation is the shift of macroscopic polarization between the ortho- and allosteric binding pockets and the intracellular G protein-binding interface.

Highlights

Accepted: 28 April 2021G protein-coupled receptors (GPCRs) are located on cell surfaces and act as communication interfaces for external stimuli exerted by structurally diverse molecules
The N- and C-terminal domains of the receptor were included to account for the drag posed by the mass of these domains and its effect on the dynamics of transmembrane helices, of which the central role in the activation mechanism was widely emphasized by previous proposals [3,4,5,6,7,8,12,13,14]
Considering that the orientation of amino acid side chains in the orthosteric binding pocket of the measurements of the μ-opioid receptor (MOP) are nearly identical in the agonist- [5,6] and antagonist-bound states [7], our results suggest that the underlying event of receptor activation is the parallel change of macroscopic polarization in a shielded central duct of the transmembrane domain

Summary

Introduction

Accepted: 28 April 2021G protein-coupled receptors (GPCRs) are located on cell surfaces and act as communication interfaces for external stimuli exerted by structurally diverse molecules. Of all prescription pharmaceuticals target members of this receptor family [1]. Application of such drugs is often limited by a number of unwanted side effects due to non-selective activation of multiple GPCRs, or multiple signaling pathways associated with one receptor. The most recent challenge of rational drug design is, to develop signaling pathway-specific, or in other words “functionally selective” GPCR agonists. To address this challenge, complete understanding of the structural mechanism of GPCR activation is necessary. Opposed to the high diversity of external activators, signaling is mediated by only a few types of G proteins, advocating that GPCR activation may follow a general mechanism

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