A small molecule enhances arrestin-3 binding to the β<sub>2</sub>-adrenergic receptor
Creators
- 1. Middle East Tech Univ, Dept Biol Sci, Ankara, Turkiye
- 2. Vanderbilt Univ, Dept Pharmacol, Nashville, TN USA
- 3. Univ Milan, Dept Chem, Via Golgi 19, Milan, Italy
- 4. CNR, Ist Sci & Tecnol Chim G Natta SCITEC, Via Mario Bianco 9, Milan, Italy
Description
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 beta 2-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.
Files
bib-ab2d1eed-8b05-407d-b9ae-90fb2a8f870d.txt
Files
(299 Bytes)
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