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

Kurt H., Akyol A., SON Ç. D., Zheng C., Gado I., Meli M., ...Daha Fazla

Communications Chemistry, cilt.8, sa.1, 2025 (SCI-Expanded, Scopus) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 8 Sayı: 1
  • Basım Tarihi: 2025
  • Doi Numarası: 10.1038/s42004-025-01581-4
  • Dergi Adı: Communications Chemistry
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Directory of Open Access Journals
  • Orta Doğu Teknik Üniversitesi Adresli: Evet

Özet

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.