A small molecule enhances arrestin-3 binding to the β2-adrenergic receptor

Date

2025-12-01

Author

Kurt, Han
Akyol, Ali
Son, Çağdaş Devrim
Zheng, Chen
Gado, Irene
Meli, Massimiliano
Ferrandi, Erica Elisa
Bassanini, Ivan
Vasile, Francesca
Gurevich, Vsevolod V.
Nebol, Aylin
Cagavi, Esra
Morra, Giulia
Sensoy, Ozge

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Excessive signaling by various GPCRs underlies a variety of human disorders. Suppression of GPCRs by “enhanced” arrestin mutants was proposed as therapy. We hypothesized that GPCR binding of endogenous arrestins can be increased by small molecules stabilizing pre-activated conformation. Using molecular dynamics, we identified potentially druggable pockets in pre-activated conformation of arrestin-3 and discovered a compound targeting one of these pockets. Saturation-transfer difference NMR data showed that the compound binds at the back loop of arrestin-3. FRET- and NanoBiT-based assays in living cells showed that the compound increased in-cell arrestin-3, but not arrestin-2, binding to basal β2-adrenergic receptor and its phosphorylation-deficient mutant, but not to muscarinic M2 receptor. These experiments demonstrated the feasibility of enhancing the binding of endogenous wild type arrestin-3 to GPCRs in a receptor-specific and arrestin-subtype selective manner.

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https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=105009893232&origin=inward
https://hdl.handle.net/11511/115345

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Department of Biology, Article