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Review
. 2018 Jul;175(14):2834-2845.
doi: 10.1111/bph.13774. Epub 2017 Apr 12.

Insights Into the Function of Opioid Receptors From Molecular Dynamics Simulations of Available Crystal Structures

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Free PMC article
Review

Insights Into the Function of Opioid Receptors From Molecular Dynamics Simulations of Available Crystal Structures

Kristen A Marino et al. Br J Pharmacol. .
Free PMC article

Abstract

The opioid receptors are key targets in the treatment of acute and chronic pain, and the development of novel analgesics with reduced side effects is crucial in the search for more effective medications. The crystal structures of opioid receptors have provided a wealth of knowledge on many aspects of opioid receptor pharmacology and function, including ligand binding poses, location of the sodium allosteric binding site, conformational changes associated with activation and putative dimeric interfaces. These crystal structures also offer a starting point for molecular dynamics (MD) simulations to capture one aspect of drug design that static structures cannot resolve, namely protein dynamics. With the increase in computing power, MD simulations of crystal structures have become an influential tool in understanding the function of GPCRs in general. Here, we discuss lessons learned from MD simulations of opioid receptor crystal structures with reference to (i) the binding pathway of sodium to its crystallographic allosteric site, (ii) the dynamics of ligand-receptor and receptor-receptor interactions, both at the ligand- and G protein-binding sites, (iii) the binding pathway and binding pose of novel ligands, and (iv) opioid receptor oligomerization.

Linked articles: This article is part of a themed section on Emerging Areas of Opioid Pharmacology. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.14/issuetoc.

Figures

Figure 1
Figure 1
(A) Comparison of the inactive crystal structure of the μ receptor (PBD:4DKL, backbone: light blue, β‐FNA: dark blue) and the activated crystal structure of the μ receptor (PDB:5C1M backbone: light green, BU72: dark green); (B) 2D structure of β‐FNA and BU72, the ligands crystallized with the inactive and activated μ receptor; (C) sodium ion (purple sphere) coordination with D2.50, S3.39, N3.35 and two water molecules (red spheres) at the allosteric binding site of the inactive δ receptor crystal structure (PDB: 4N6H, backbone: pink, naltrindole: dark pink) compared with the collapsed sodium binding site of the activated μ receptor crystal structure (light green).
Figure 2
Figure 2
(A) Close‐up of the binding pockets of inactive and activated μ receptor crystal structures. Focus is on the salt bridges (yellow, dotted lines) formed by the amino group of β‐FNA (dark blue) and BU72 (dark green) and the side chain of D3.32 of the inactive (light blue) and activated (light green) crystal structures, respectively, as well as the hydrophobic interaction between W6.48 and β‐FNA; (B) residues of TM6 and TM7 used to calculate helix bending in (Cheng et al., 2016b); (C) residues involved in the ionic lock in inactive and activated μ receptor crystal structures. Shown as dotted lines are the salt bridge (orange) between D3.49 and R3.50 and the hydrogen bond (yellow) between T6.34 with R3.50 in the inactive μ receptor crystal structure, as well as the hydrogen bond (yellow) formed between Y5.58 and R3.50 in the activated crystal structure of the μ receptor.
Figure 3
Figure 3
(A) Structure of TRV‐130, a biased agonist for the μ receptor, and (B) predicted binding poses of TRV‐130 (pink and light orange) in the μ receptor orthosteric binding site overlaid on the receptor activated crystal structure (light green) bound to BU72 (dark green). The salt‐bridge between the amino group of BU72 and D3.32 is shown as a yellow dotted line. The residues that interact with TRV‐130 within a 4 Å distance cut‐off are labelled.
Figure 4
Figure 4
An extracellular view of the two lowest energy binding poses of BMS‐986187 in red (pose 1) and blue (pose 2) bound to the δ receptor. The agonist, SNC‐80, is in orange. Water molecules which participate in water‐mediated hydrogen bonds between BMS‐986187 and the receptor are shown as red spheres. Residues that interact with both pose 1 and pose 2 are labelled. Adapted with permission from Shang et al. (2016) Proposed mode of binding and action of positive allosteric modulators at opioid receptors. ACS Chemical Biology, 11: 1220‐9. Copyright 2016 American Chemical Society.
Figure 5
Figure 5
The three putative dimeric interfaces seen in opioid receptor inactive crystal structures (A) κ receptor (KOR) TM1,2,H8/TM1,2,H8, (B) μ receptor (MOR) TM1,2,H8/TM1,2,H8 and (C) μ receptor (MOR) TM5,6/TM5,6. The top row shows the interface with protomer A in pink and protomer B in green. The bottom row shows a cross section of the interface. The red spheres represent the Cα atoms of residues involved in cross‐interface contacts, where a contact is considered to be formed between two residues if their Cα atoms are within 8 Å of each other.

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