Small-molecule modulation of β-arrestins.

Authors

Alem W Kahsai, Natalia Pakharukova, Henry Y Kwon, Kunal S Shah, Caroline T Del Real, Bowie N Shreiber, Jason G Liang-Lin, Paul J Shim, Mason A Lee, Van A Ngo, Allison M Schwalb, Uyen Pham, Anand Chundi, Haoran Jiang, Emmanuel Flores-Espinoza, Samuel Liu, Preston C Nibley, Dana K Bassford, Hyunggu Hahn, Cal A Kunzle, Brittany N Thomas, Jihee Kim, Yang Zhou, Jialu Wang, Xingdong Zhang, Jeffrey S Smith, Lindsay A M Rein, Alex R B Thomsen, Sudha K Shenoy, Sudarshan Rajagopal, Lei Shi, Seungkirl Ahn, Howard A Rockman, Ali Masoudi, Robert J Lefkowitz

Published in

Nature. Jun 24, 2026. Epub Jun 24, 2026.

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^1-3. 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.

PMID:
42343124
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.

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