Structural insights into the binding modes of Arrestin-3 finger loop to the neuropeptide Y₁ and Y₂ receptors

The interaction of the finger loop sequence of arrestin-3 with the neuropeptide Y₁ and Y₂ G protein-coupled receptors was studied. In cell assays, the finger loop part of arrestin was shown to be essential for Y₂R internalization, but had no relevance for the interaction with Y₁R. Here, we combined experimental data from nanoBRET, EPR, and NMR spectroscopy studies using a small library of NMR- and EPR-labeled finger loop peptides. Computer models of arrestin interacting with both receptors were built using AlphaFold2 and filtered by experimental constraints. Overall, Y₁ and Y₂ receptors show different binding modalities with the interacting finger loop region. In the interaction with Y₁ receptor, the finger loop features a tail conformation critical for binding but also optional interactions. The Y₂ receptor showed fewer contacts with the finger loop and two different conformations were found, which allow for higher intrinsic flexibility of this arrestin-3 segment.