NEUROPEPTIDE-Y N-TERMINAL DELETION FRAGMENTS - CORRELATION BETWEEN SOLUTION STRUCTURE AND RECEPTOR-BINDING ACTIVITY AT Y-1 RECEPTORS IN RAT-BRAIN CORTEX

Na-Acetyl (Ac), N-terminal deletion fragments of porcine neuropeptide Y (NPY) have been synthesized and characterized for solution conformat ion properties by circular dichroism and for receptor binding activity at benextramine-sensitive Y-1 binding sites in rat brain cortex. Sequ ential deletion of Tyr(1), Pro(2), and Ser(3) had no effect on the str uctural (alpha-helical content of 32.5, 30.6, and 30.7%, respectively, at 1 x 10(-5) M) or aggregation (monomer to dimer transition for N-al pha-AC-NPY3-36 and N-alpha-AC-NPY4-36) properties of NPY. In contrast, deletion of Tyr(1) decreased receptor binding activity in rat brain c ortex by 4-fold (IC50 = 13.0 nM versus 3.75 nM for NPY), but further d eletion of Pro(2)-Ser(3) had no additional detrimental effect on recep tor binding activity relative to the desTyr(1) analog. Thus, Pro(2) an d Ser(3) do not contribute either to the stability of the NPY tertiary structure nor directly to the receptor-ligand interactions. Additiona l removal of N-terminal amino acids Lys(4)-Pro(5) decreased the helica l content and abolished aggregation to a dimeric form of the resultant analog, results suggesting that the residues around Pro(5) are import ant for formation of NPY's compact, pancreatic polypeptide (PP)-fold s tructure. This loss in structure also correlated with a further 2-3-fo ld drop in receptor binding activity. These structure-activity correla tions provide evidence for the importance of the PP-fold structure in the activity of NPY at Y-1 receptors in rat brain cortex.