Binding of Natural Peptide Ligands to the Neuropeptide Y₅ Receptor

Abstract

The binding mode of natural peptide ligands to the Y 5 Gprotein-coupled receptor (Y 5 R), an attractive therapeutic target for the treatment of obesity,islargely unknown. Here,we apply complementary biochemical and computational approaches,i ncluding scanning of the receptor surface with ag enetically encoded crosslinker,A la-scanning of the ligand and double-cycle mutagenesis,t om ap interactions in the ligand-receptor interface and build as tructural model of the NPY-Y 5 Rc omplex guided by the experimental data. In the model, the carboxyl (C)-terminus of bound NPY is placed close to the extracellular loop (ECL) 3, whereas the characteristic a-helical segment of the ligand drapes over ECL1 and is tethered towards ECL2 by ah ydrophobic cluster.W ef urther show that the other two natural ligands of Y 5 R, peptide YY (PYY) and pancreatic polypeptide (PP) dock to the receptor in asimilar pose.