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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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

摘要

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.