The Role of Water and Sodium Ions in the Activation of the μ‐Opioid Receptor

Abstract

Dual effect of sodium ions: The activation of G-protein-coupled receptors depends on the presence of water molecules inside the receptor and also on allosteric interactions. The binding of sodium ions to the allosteric site of the μ opioid receptor was studied by microsecond molecular dynamics simulations and their seemingly contradictory roles in preventing ligand binding and facilitating receptor activation were explained.

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

“…In our present work we found that GPCRs in their activated state comprise a continuous internal TM water channel. In our previous projects we investigated how water molecules enter the interior of the receptor 8,29 . For formyl peptide receptor 1 (FPR 1 ) and opioid receptors (ORs), using microsecond MD simulations, we showed that the influx of water molecules occurs towards the allosteric site, which is different from that in the human sphingosine-1-phosphate receptor 1 (S1PR 1 ) 30 .…”

“…Distinct conformational changes occur during activation of these receptors, including reorganizations of inner protein hydrogen bonding networks, which could be in contact with internal waters 5,6 . An important step forward came from the recent high-resolution crystal structures of the A 2A adenosine receptor (A 2A R) and the delta opioid receptor (dOR), which revealed internal ordered water molecules that could be crucial for GPCR activation 7,8 . On the basis of their crystal structures, Liu et al 7 proposed that the A 2A R in the non-activated state contains a nearly continuous internal water channel, which is disrupted in the activated receptor.…”

“…Notably, the details of how the intrinsic water molecules couple to the protein structure and thereby affect GPCR activation at the atomic level cannot be solved by static X-ray structures. Alternatively, molecular dynamics (MD) simulations can resolve atomic details of structural transitions of receptors and their internal waters, which are experimentally not accessible [8][9][10][11] . Here, by using a total of 32-ms all-atom MD simulations, we studied with high spatial and temporal resolution important steps during the activation of three different receptors from class A GPCRs to elucidate how water molecules enter the inner space of a receptor, couple to and influence this protein's structural transitions.…”

Modulation of GPCRs by monovalent cations and anions

“…In this binding trajectory, the cation has to pass the orthosteric ligand binding site (Selent et al 2010;Yuan et al 2013;Wittmann et al 2014b). An entry of the monovalent cation coming from the intracellular side has not been described until now and is unlikely because the intracellular side of the receptor is, compared with the extracellular side, more positively charged.…”

“…The crystal structures show that the Na + binds in an allosteric binding site near the highly conserved Asp 2.50 (Liu et al 2012;Fenalti et al 2014;Miller-Gallacher et al 2014;Katritch et al 2014). Based on the simulation data available in literature, so far it can be assumed that the monovalent cations bind to the allosteric binding site by coming from the extracellular side (Selent et al 2010;Yuan et al 2013;Wittmann et al 2014b).…”