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DOE OSTI · 3385011

Small-molecule modulation of β-arrestins

Kahsai, Alem W. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000192724484)·Pakharukova, Natalia [Duke University, Durham, NC (United States). Medical Center]·Kwon, Henry Y. [Duke University, Durham, NC (United States). Medical Center; Henry Ford Hospital, Detroit, MI (United States)] (ORCID:0000000170319023)·Shah, Kunal S. [Duke University, Durham, NC (United States). Medical Center; Cedars‐Sinai Medical Center, Los Angeles, CA (United States)] (ORCID:0000000199063025)·del Real, Caroline T. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0009000274664435)·Shreiber, Bowie N. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000331344431)·Liang-Lin, Jason G. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000342776694)·Shim, Paul J. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000266108378)·Lee, Mason A. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000187723567)·Ngo, Van A. [Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). National Center for Computational Sciences (NCCS)] (ORCID:0000000183501203)·Schwalb, Allison M. [Duke University, Durham, NC (United States). Medical Center]·Pham, Uyen [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000220386794)·Chundi, Anand [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000181487479)·Jiang, Haoran [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000159163072)·Flores-Espinoza, Emmanuel [New York University (NYU), NY (United States). College of Dentistry] (ORCID:0000000278897458)·Liu, Samuel [Duke University, Durham, NC (United States). Medical Center]·Nibley, Preston C. [Duke University, Durham, NC (United States). Medical Center]·Bassford, Dana K. [Duke University, Durham, NC (United States). Medical Center]·Hahn, Hyunggu [New York University (NYU), NY (United States). College of Dentistry] (ORCID:0000000335327671)·Kunzle, Cal A. [Duke University, Durham, NC (United States). Medical Center]·Thomas, Brittany N. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000183177538)·Kim, Jihee [Duke University, Durham, NC (United States). Medical Center]·Zhou, Yang [Duke University, Durham, NC (United States). Medical Center]·Wang, Jialu [Duke University, Durham, NC (United States). Medical Center]·Zhang, Xingdong [Duke University, Durham, NC (United States). Medical Center]·Smith, Jeffrey S. [Duke University, Durham, NC (United States). Medical Center; Massachusetts General Hospital, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)]·Rein, Lindsay A. M. [Duke University, Durham, NC (United States). Medical Center]·Thomsen, Alex R. B. [New York University (NYU), NY (United States). College of Dentistry] (ORCID:0000000316388911)·Shenoy, Sudha K. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000225654663)·Rajagopal, Sudarshan [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000234435040)·Shi, Lei [National Institutes of Health (NIH), Baltimore, MD (United States)] (ORCID:000000024137096X)·Ahn, Seungkirl [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000156813789)·Rockman, Howard A. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000329211584)·Masoudi, Ali [Duke University, Durham, NC (United States). Medical Center]·Lefkowitz, Robert J. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000314727545)
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Abstract

β-Arrestins are multifunctional regulators of G-protein-coupled receptor (GPCR) signalling and orchestrate diverse downstream signalling events and physiological responses across the GPCR superfamily. Although GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GPCR kinases, direct chemical tools to modulate β-arrestin activities have remained conspicuously absent. Here we report the identification of small-molecule inhibitors that selectively target β-arrestins and delineate their mechanism of action through integrated pharmacological, biochemical, biophysical and structural analyses. These inhibitors disrupt β-arrestin engagement with agonist-activated GPCRs, impairing desensitization, internalization and β-arrestin-dependent physiological functions while sparing G protein–receptor coupling. Cryo-electron microscopy, molecular dynamics simulations and structure-guided mutagenesis reveal that one modulator, Cmpd-5, engages a pocket within the central crest of β-arrestin1 formed by the middle, C and lariat loops, a critical receptor-binding interface, stabilizing a distinct conformation that is incompatible with full β-arrestin–receptor engagement. Together, these findings establish a mechanistic framework for β-arrestin modulation, reveal a novel allosteric site for structure-based drug design, and open new avenues for transducer-targeted, pathway-specific GPCR therapeutic agents.

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BibTeXRIS

Kahsai, Alem W. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000192724484), Pakharukova, Natalia [Duke University, Durham, NC (United States). Medical Center], Kwon, Henry Y. [Duke University, Durham, NC (United States). Medical Center; Henry Ford Hospital, Detroit, MI (United States)] (ORCID:0000000170319023), Shah, Kunal S. [Duke University, Durham, NC (United States). Medical Center; Cedars‐Sinai Medical Center, Los Angeles, CA (United States)] (ORCID:0000000199063025), del Real, Caroline T. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0009000274664435), Shreiber, Bowie N. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000331344431), Liang-Lin, Jason G. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000342776694), Shim, Paul J. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000266108378), Lee, Mason A. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000187723567), Ngo, Van A. [Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). National Center for Computational Sciences (NCCS)] (ORCID:0000000183501203), Schwalb, Allison M. [Duke University, Durham, NC (United States). Medical Center], Pham, Uyen [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000220386794), Chundi, Anand [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000181487479), Jiang, Haoran [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000159163072), Flores-Espinoza, Emmanuel [New York University (NYU), NY (United States). College of Dentistry] (ORCID:0000000278897458), Liu, Samuel [Duke University, Durham, NC (United States). Medical Center], Nibley, Preston C. [Duke University, Durham, NC (United States). Medical Center], Bassford, Dana K. [Duke University, Durham, NC (United States). Medical Center], Hahn, Hyunggu [New York University (NYU), NY (United States). College of Dentistry] (ORCID:0000000335327671), Kunzle, Cal A. [Duke University, Durham, NC (United States). Medical Center], Thomas, Brittany N. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000183177538), Kim, Jihee [Duke University, Durham, NC (United States). Medical Center], Zhou, Yang [Duke University, Durham, NC (United States). Medical Center], Wang, Jialu [Duke University, Durham, NC (United States). Medical Center], Zhang, Xingdong [Duke University, Durham, NC (United States). Medical Center], Smith, Jeffrey S. [Duke University, Durham, NC (United States). Medical Center; Massachusetts General Hospital, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)], Rein, Lindsay A. M. [Duke University, Durham, NC (United States). Medical Center], Thomsen, Alex R. B. [New York University (NYU), NY (United States). College of Dentistry] (ORCID:0000000316388911), Shenoy, Sudha K. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000225654663), Rajagopal, Sudarshan [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000234435040), Shi, Lei [National Institutes of Health (NIH), Baltimore, MD (United States)] (ORCID:000000024137096X), Ahn, Seungkirl [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000156813789), Rockman, Howard A. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000329211584), Masoudi, Ali [Duke University, Durham, NC (United States). Medical Center], Lefkowitz, Robert J. [Duke University, Durham, NC (United States). Medical Center] (ORCID:0000000314727545). 2026-06-24. Small-molecule modulation of β-arrestins. https://doi.org/10.1038/s41586-026-10683-5

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