Mechanism of negative µ-opioid receptor modulation by sodium ions

TY - JOUR

T1 - Mechanism of negative µ-opioid receptor modulation by sodium ions

AU - Thomson, Neil J.

AU - Zachariae, Ulrich

N1 - Publisher Copyright: © 2024 The Author(s)

PY - 2025/1/2

Y1 - 2025/1/2

N2 - Negative allosteric modulation of G-protein coupled receptors (GPCRs) by Na+ ions was first described in the 1970s for opioid receptors (ORs) and has subsequently been detected for most class A GPCRs. In high-resolution structures of inactive-state class A GPCRs, a Na+ ion binds to a conserved pocket near residue D2.50, whereas active-state structures of GPCRs are incompatible with Na+ binding. Correspondingly, Na+ diminishes agonist affinity, stabilizes the receptors in the inactive state, and reduces basal signalling. We applied a mutual-information based analysis to µs-timescale biomolecular simulations of the µ-OR. Our results reveal that Na+ binding is coupled to a water wire linking the Na+ binding site with the agonist binding pocket and to rearrangements in polar networks propagating conformational changes to the agonist and G-protein binding sites. These findings provide a new mechanistic link between the presence of the ion, altered agonist affinity, receptor deactivation, and lowered basal signalling levels.

AB - Negative allosteric modulation of G-protein coupled receptors (GPCRs) by Na+ ions was first described in the 1970s for opioid receptors (ORs) and has subsequently been detected for most class A GPCRs. In high-resolution structures of inactive-state class A GPCRs, a Na+ ion binds to a conserved pocket near residue D2.50, whereas active-state structures of GPCRs are incompatible with Na+ binding. Correspondingly, Na+ diminishes agonist affinity, stabilizes the receptors in the inactive state, and reduces basal signalling. We applied a mutual-information based analysis to µs-timescale biomolecular simulations of the µ-OR. Our results reveal that Na+ binding is coupled to a water wire linking the Na+ binding site with the agonist binding pocket and to rearrangements in polar networks propagating conformational changes to the agonist and G-protein binding sites. These findings provide a new mechanistic link between the presence of the ion, altered agonist affinity, receptor deactivation, and lowered basal signalling levels.

KW - GPCRs

KW - PENSA

KW - allostery

KW - antagonism

KW - biomolecular simulations

KW - cell surface receptors

KW - microswitches

KW - mutual information

KW - protein-internal water

KW - sodium effect

UR - https://www.scopus.com/pages/publications/85210736668

U2 - 10.1016/j.str.2024.10.023

DO - 10.1016/j.str.2024.10.023

M3 - Article

C2 - 39536757

SN - 0969-2126

VL - 33

SP - 196-205.e2

JO - Structure

JF - Structure

IS - 1

ER -