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

Abstract

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 μ 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.

Allostery at opioid receptors: modulation with small molecule ligands

“…Using molecular docking, Bartuzi et al () obtained several poses for BMS‐986122 within the μ‐receptor although two had very similar orientations and interaction energies. These data indicated an allosteric site involving amino acids above the orthosteric binding pocket and towards the extracellular surface in TM domains II and VII (Figure ).…”

“…Inactive state μ‐receptors (pdb 4DKL; Huang et al , ) and inactive state δ‐ receptors (pdb 4N6H; Fenalti et al , ) were aligned. The residues proposed (Bartuzi et al , ; Shang et al , ) to be involved in allosteric ligand binding are highlighted in green for the μ‐receptor and orange for the δ‐ receptor. (A) view of aligned receptors from the extracellular side, (B) side view.…”

Receptor antagonism/agonism can be uncoupled from pharmacoperone activity

“…Additionally, it appears that pharmacoperones that rescue one mutant of a particular protein, rescue many (7, 8), suggesting that these agents stabilize one or more regions that are needed in a particular conformation to pass the scrutiny of the cellular quality control system. The presence of more than a single binding site that impacts on a GPCR is not novel (24), but we believe that the present study is the first to identify small molecules that impact receptor trafficking without competing for binding at the native ligand binding site.…”

Structural dynamics of non-synonymous SNPs of histone methyltransferase EZH2 involved in Weaver Syndrome

“…The peptide binding pocket in the SET-domain of EZH2 has composed of 310 helix, ext. Principal component analysis (PCA) is a multivariate statistical technique for protein dynamics and can be used to study the molecular motions in the smallest spatial scale [41,42]. PC analysis of EZH-WT structure has shown more profound motions of coils in the acid orientations in the binding pocket strongly influence the peptide recognition [43].…”