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Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors

Shang, Y.; Yeatman, H.R.; Provasi, D.; Alt, A.; Christopoulos, A.; Canals, M.; Filizola, M.


Y. Shang

H.R. Yeatman

D. Provasi

A. Alt

A. Christopoulos

M. Filizola


Available crystal structures of opioid receptors provide a high-resolution picture of ligand binding at the primary ("orthosteric") site, that is, the site targeted by endogenous ligands. Recently, positive allosteric modulators of opioid receptors have also been discovered, but their modes of binding and action remain unknown. Here, we use a metadynamics-based strategy to efficiently sample the binding process of a recently discovered positive allosteric modulator of the δ-opioid receptor, BMS-986187, in the presence of the orthosteric agonist SNC-80, and with the receptor embedded in an explicit lipid-water environment. The dynamics of BMS-986187 were enhanced by biasing the potential acting on the ligand-receptor distance and ligand-receptor interaction contacts. Representative lowest-energy structures from the reconstructed free-energy landscape revealed two alternative ligand binding poses at an allosteric site delineated by transmembrane (TM) helices TM1, TM2, and TM7, with some participation of TM6. Mutations of amino acid residues at these proposed allosteric sites were found to either affect the binding of BMS-986187 or its ability to modulate the affinity and/or efficacy of SNC-80. Taken together, these combined experimental and computational studies provide the first atomic-level insight into the modulation of opioid receptor binding and signaling by allosteric modulators. © 2016 American Chemical Society.


Shang, Y., Yeatman, H., Provasi, D., Alt, A., Christopoulos, A., Canals, M., & Filizola, M. (2016). Proposed Mode of Binding and Action of Positive Allosteric Modulators at Opioid Receptors. ACS Chemical Biology, 11(5), 1220-1229.

Journal Article Type Article
Acceptance Date Feb 3, 2016
Online Publication Date Feb 17, 2016
Publication Date May 20, 2016
Deposit Date Jan 17, 2020
Journal ACS Chemical Biology
Print ISSN 1554-8929
Electronic ISSN 1554-8937
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 11
Issue 5
Pages 1220-1229
Keywords 4 [alpha (4 allyl 2,5 dimethyl 1 piperazinyl) 3 methoxybenzyl] n,n diethylbenzamide; amino acid; bms 986187; lipid; opiate receptor; radioligand; tumor necrosis factor related apoptosis inducing ligand receptor; unclassified drug; [3,3,6,6tetramethyl 9 [4
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