2. Academic Validation
  3. A small molecule enhances arrestin-3 binding to the β2-adrenergic receptor

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

  • Commun Chem. 2025 Jul 1;8(1):194. doi: 10.1038/s42004-025-01581-4.
Han Kurt # 1 2,  Ali Akyol # 3,  Cagdas Devrim Son 3,  Chen Zheng 4,  Irene Gado 5,  Massimiliano Meli 6,  Erica Elisa Ferrandi 6,  Ivan Bassanini 6,  Francesca Vasile 5,  Vsevolod V Gurevich 4,  Aylin Nebol 7 8 9,  Esra Cagavi 7 8 9,  Giulia Morra 10,  Ozge Sensoy 11 12
Affiliations

Affiliations

  • 1 Istanbul Medipol University, Graduate School of Engineering and Natural Sciences, Istanbul, Turkey.
  • 2 University of Cagliari, Department of Physics, Cittadella Universitaria, Monserrato (CA), Italy.
  • 3 The Middle East Technical University, Department of Biological Sciences, Ankara, Turkey.
  • 4 Vanderbilt University, Department of Pharmacology, Nashville, TN, USA.
  • 5 University of Milano, Department of Chemistry, via Golgi 19, Milano, Italy.
  • 6 Consiglio Nazionale delle Ricerche, Istituto di Scienze e Tecnologie Chimiche "G. Natta" SCITEC, via Mario Bianco 9, Milano, Italy.
  • 7 Istanbul Medipol University, Research Institute for Health Sciences and Technologies (SABITA), Regenerative and Restorative Medical Research Center (REMER), Istanbul, Turkey.
  • 8 Istanbul Medipol University, Institute for Health Sciences, Medical Biology and Genetics Program, Istanbul, Turkey.
  • 9 Istanbul Medipol University, School of Medicine, Department of Medical Biology, Istanbul, Turkey.
  • 10 Consiglio Nazionale delle Ricerche, Istituto di Scienze e Tecnologie Chimiche "G. Natta" SCITEC, via Mario Bianco 9, Milano, Italy. giulia.morra@cnr.it.
  • 11 Istanbul Medipol University, Research Institute for Health Sciences and Technologies (SABITA), Regenerative and Restorative Medical Research Center (REMER), Istanbul, Turkey. osensoy@medipol.edu.tr.
  • 12 Istanbul Medipol University, School of Engineering and Natural Sciences, Department of Biomedical Engineering, Istanbul, Turkey. osensoy@medipol.edu.tr.
  • # Contributed equally.
PMID: 40593109 DOI: 10.1038/s42004-025-01581-4
Abstract

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.

Figures
Products