Interplay between Two Allosteric Sites and Their Influence on Agonist Binding in Human μ Opioid Receptor

Allostery is a widespread mechanism that allows for precise protein tuning. Its underlying mechanisms are elusive, particularly when there are multiple allosteric sites at the protein. This concerns also G-protein-coupled receptors (GPCRs), which are targets for a vast part of currently used drugs. To address this issue, we performed molecular dynamics simulations of a GPCR human mu opioid receptor (MOR) in a native-like environment, with full agonist (R)-methadone; Na+ ions, and a positive modulator BMS986122 in various configurations. We found that MOR's seventh transmembrane helix: (TM VII) is central for allosteric signal transmission, and modulators affect its bending and rotation. The PAM stabilizes favorable agonist interactions, while Na+ tends to disrupt agonist binding. We identified two residues involved in allosteric signal-transmission: Trp 7.35 at the top and Tyr 7.53 at the bottom of TM VII.