Small-molecule modulation of β-arrestins
. 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.
Authors
- Ali Masoudi (ORCID: https://orcid.org/0000-0001-5691-9495)
- Kunal S. Shah (ORCID: https://orcid.org/0000-0001-9906-3025)
- Jason G. Liang-Lin (ORCID: https://orcid.org/0000-0003-4277-6694)
- Natalia Pakharukova (ORCID: https://orcid.org/0000-0002-8363-6105)
- Samuel Liu (ORCID: https://orcid.org/0000-0001-8339-0080)
- Brittany N. Thomas (ORCID: https://orcid.org/0000-0001-8317-7538)
- Emmanuel Flores-Espinoza (ORCID: https://orcid.org/0000-0002-7889-7458)
- Jihee Kim (ORCID: https://orcid.org/0000-0002-3875-1083)
- A. Thomsen (ORCID: https://orcid.org/0000-0003-1638-8911)
- Lei Shi (ORCID: https://orcid.org/0000-0002-4137-096X)
- Sudarshan Rajagopal (ORCID: https://orcid.org/0000-0002-3443-5040)
- Paul J. Shim (ORCID: https://orcid.org/0000-0002-6610-8378)
- Jeffrey S. Smith (ORCID: https://orcid.org/0000-0003-2840-2899)
- Uyên Phương Phạm (ORCID: https://orcid.org/0000-0002-2038-6794)
- Anand Chundi (ORCID: https://orcid.org/0000-0001-8148-7479)
- Van A. Ngo (ORCID: https://orcid.org/0000-0001-8350-1203)
- Hyunggu Hahn (ORCID: https://orcid.org/0000-0003-3532-7671)
- Sudha K. Shenoy (ORCID: https://orcid.org/0000-0002-2565-4663)
- Henry Y. Kwon (ORCID: https://orcid.org/0000-0001-7031-9023)
- Seungkirl Ahn (ORCID: https://orcid.org/0000-0001-5681-3789)
- Yang Zhou (ORCID: https://orcid.org/0000-0002-9217-5208)
- Howard A. Rockman (ORCID: https://orcid.org/0000-0003-2921-1584)
- Haoran Jiang (ORCID: https://orcid.org/0000-0001-5916-3072)
- Mason Lee (ORCID: https://orcid.org/0000-0001-8772-3567)
- Robert J. Lefkowitz (ORCID: https://orcid.org/0000-0003-1472-7545)
- Alem W. Kahsai (ORCID: https://orcid.org/0000-0001-9272-4484)
- Allison M. Schwalb (ORCID: https://orcid.org/0000-0002-1905-8988)
- Bowie N. Shreiber (ORCID: https://orcid.org/0000-0003-3134-4431)
- Preston C. Nibley (ORCID: https://orcid.org/0009-0002-1140-1531)
- Dana K. Bassford (ORCID: https://orcid.org/0009-0005-8474-5046)
- Jialu Wang (ORCID: https://orcid.org/0000-0002-0927-9242)
- Lindsay Rein (ORCID: https://orcid.org/0000-0002-9888-4814)
- Xingdong Zhang (ORCID: https://orcid.org/0000-0003-0716-6815)
- Cal A. Kunzle
- Caroline T. del Real (ORCID: https://orcid.org/0009-0002-7466-4435)
Institutions
- Cedars-Sinai Medical Center (US)
- Oak Ridge National Laboratory (US)
- National Institute on Drug Abuse (US)
- Howard Hughes Medical Institute (US)
- Duke University (US)
- Henry Ford Hospital (US)
- Massachusetts General Hospital (US)
- Duke Medical Center (US)
- Duke University Hospital (US)
- New York University (US)
Publication Details
- Journal
- Nature
- Published
- 2026-06-24
- DOI
- https://doi.org/10.1038/s41586-026-10683-5
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00