Abstract
Positive allosteric modulators (PAMs) of the μ opioid receptor (MOR) offer a promising path toward safer opioid therapeutics, yet their mechanisms of action remain poorly understood. Here, we uncover the structural and mechanistic basis of BMS-986187, a chemically distinct MOR PAM with in vivo efficacy, using an integrated approach combining cryogenic electron microscopy (cryo-EM), molecular dynamics (MD) simulations, signaling assays, and site-directed mutagenesis. We identify a previously uncharacterized allosteric site for BMS-986187, a lipid-facing pocket formed by MOR transmembrane helices 2, 3, and 4, distinct from sites occupied by other known MOR PAMs or negative allosteric modulators. BMS-986187 engages both receptor residues and a neighboring cholesterol molecule, suggesting a cooperative ligand–lipid mechanism. Our studies pinpoint residues essential for allosteric modulation, while information-theory analysis of MD trajectories uncovers specific allosteric communication pathways linking the PAM site to both the orthosteric agonist DAMGO and the G protein interface. Together, these findings redefine the landscape of MOR allosteric modulation by revealing a previously unknown binding site, a potentially lipid-sensitive allosteric mechanism, and the molecular wiring of long-range communication within MOR. This work provides a molecular framework for the rational design of PAMs targeting opioid receptors with improved precision and possible therapeutic potential.
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Acknowledgements
This work was supported by NIH grants R01DA058681 (D.W.) and R01DA063209 (M.F.), an Irma T. Hirschl/Monique Weill-Caulier Trust Research Award (D.W.), NIH F31 fellowship MH132317 and T32 Training Grant GM062754 (A.L.W), and T32 Training Grant DA053558 (G.Z.). Some of this work was performed at the National Center for cryo-EM Access and Training (NCCAT) and the Simons Electron Microscopy Center located at the New York Structural Biology Center, supported by the NIH Common Fund Transformative High Resolution Cryo-Electron Microscopy program (U24 GM129539,) and by grants from the Simons Foundation (SF349247) and NY State Assembly. We further acknowledge cryo-EM resources at the National Resource for Automated Molecular Microscopy located at the New York Structural Biology Center, supported by grants from the Simons Foundation (SF349247), NYSTAR, and the NIH National Institute of General Medical Sciences (GM103310) with additional support from Agouron Institute (F00316) and NIH (OD019994). Computational work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai and supported by the Clinical and Translational Science Awards (CTSA) grant UL1TR004419 from the National Center for Advancing Translational Sciences. Computations reported in this paper were supported by the Office of Research Infrastructure of the National Institutes of Health under award number S10OD026880 and S10OD030463. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We would also like to acknowledge T. Che for providing the MOR PRESTO-Tango construct, O. Clarke for assessing the quality of our structures, and J. McCorvy for critical evaluation of the manuscript.
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Zhang, H., Konovalov, K., Parpounas, A.K. et al. Structural and dynamic studies uncover a distinct allosteric modulatory site at the µ-opioid receptor. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72633-z
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DOI: https://doi.org/10.1038/s41467-026-72633-z
