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Although GPCR pharmacology has advanced to target orthosteric and allosteric sites, as well as G proteins and GPCR kinases, direct chemical tools to modulate \u03b2-arrestin activities have remained conspicuously absent. Here we report the identification of small-molecule inhibitors that selectively target \u03b2-arrestins and delineate their mechanism of action through integrated pharmacological, biochemical, biophysical and structural analyses. These inhibitors disrupt \u03b2-arrestin engagement with agonist-activated GPCRs, impairing desensitization, internalization and \u03b2-arrestin-dependent physiological functions while sparing G protein\u2013receptor 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 \u03b2-arrestin1 formed by the middle, C and lariat loops, a critical receptor-binding interface, stabilizing a distinct conformation that is incompatible with full \u03b2-arrestin\u2013receptor engagement. Together, these findings establish a mechanistic framework for \u03b2-arrestin modulation, reveal\u00a0a novel allosteric site for structure-based drug design, and open new avenues for transducer-targeted, pathway-specific GPCR therapeutic agents.\n                  <\/jats:p>","DOI":"10.1038\/s41586-026-10683-5","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T15:02:34Z","timestamp":1782313354000},"page":"770-779","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Small-molecule modulation of \u03b2-arrestins"],"prefix":"10.1038","volume":"656","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9272-4484","authenticated-orcid":false,"given":"Alem 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