Neuropeptide Y (NPY) is a 36-amino-acid peptide member of a family also including peptide YY and pancreatic polypeptide which are all ligands to Gi/Go coupled receptors. NPY regulates several fundamental biologic functions including appetite/satiety, sex and reproduction, learning and memory, cardiovascular and renal function and the immune function. The mesenteric circulation is a major source of NPY in the blood in man and this peptide is considered a key regulator of the gut-brain cross-talk. A progressive rise in circulating NPY accompanies the progression of CKD toward kidney failure and NPY robustly predicts cardiovascular events in this population. Furthermore, NPY is suspected as a possible player in the accelerated cognitive function decline and dementia in patients with CKD and in dialysis patients. In theory, Interfering with the NPY system has relevant potential for the treatment of diverse diseases from cardiovascular and renal diseases to diseases of the central nervous system. Pharmaceutical formulations for effective drug delivery and cost as well as the complexity of diseases potentially addressable by NPY/NPY antagonists have been a problem until now. This in part explains the slow progress of knowledge about the NPY system in the clinical arena. There is now a renewed research interest on the NPY system in psycho pharmacology and in pharmacology in general and new studies and a new breed of clinical trials may eventually bring the expected benefits in human health by drugs interfering with this system.

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.

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.