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.