Molecular characterization of the ligand-receptor interaction of the neuropeptide Y family

Abstract

Neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) belong to the NPY hormone family and activate a class of receptors called the Y-receptors, and also belong to the large superfamily of the G-protein coupled receptors. Structure-affinity and structure-activity relationship studies of peptide analogs, combined with studies based on site-directed mutagenesis and anti-receptor antibodies, have given insight into the individual characterization of each receptor subtype relative to its interaction with the ligand, as well as to its biological function. A number of selective antagonists at the Y1-receptor are available whose structures resemble that of the C-terminus of NPY. Some of these compounds, like BIBP3226, BIBO3304 and GW1229, have recently been used for in vivo investigations of the NPY-induced increase in food intake. Y2-receptor selective agonists are the analog cyclo-(28/32)-Ac-[Lys28-Glu32]-(25-36)-pNPY and the TASP molecule containing two units of the NPY segment 21-36. Now the first antagonist with nanomolar affinity for the Y2-receptor is also known, BIIE0246. So far, the native peptide PP has been shown to be the most potent ligand at the Y4-receptor. However, by the design of PP/NPY chimera, some analogs have been found that bind not only to the Y4-, but also to the Y5-receptor with subnanomolar affinities, and are as potent as NPY at the Y1-receptor. For the characterization of the Y5-receptor in vitro and in vivo, a new class of highly selective agonists is now available. This consists of analogs of NPY and of PP/NPY chimera which all contain the motif Ala31-Aib32. This motif has been shown to induce a 3(10)-helical turn in the region 28-31 of NPY and is suggested to be the key motif for high Y5-receptor selectivity. The results of feeding experiments in rats treated with the first highly specific Y5-receptor agonists support the hypothesis that this receptor plays a role in the NPY-induced stimulation of food intake. In conclusion, the selective compounds for the different Y receptor subtypes known so far are promising tools for a better understanding of the physiological properties of the hormones of the NPY family and related receptors.

Novel analogues of neuropeptide Y with a preference for the Y1‐receptor

“…This suggests an important contribution of direct interactions of the amino acids with the receptor. However, previous results that high a helicity favours binding to the Y 1 -receptor [46] could be confirmed, because no high affinity ligand at the Y 1 -receptor displayed an a helical content , 30%. Nevertheless, unfavourable direct ligand± receptor interaction reduces binding significantly despite suitable secondary structure, as shown for [Trp31]pNPY (27) This work presents the first NPY analogues with preference to the Y 1 -receptor, gives information about the importance of distinct amino acid positions for binding to the Y-receptor subtypes, provides information for the synthesis of nonpeptide ligands to the Y-receptors and is therefore a further step on the search for highly selective Y-receptor ligands.…”

“…Exchange of each residue of NPY individually by l-Ala revealed that the most sensitive positions are: Pro2, Pro5, Arg19, Tyr20 and the C-terminal positions 27±36, especially the two Arg residues at positions 33 and 35 [45]. The importance of the Pro residues 2 and 5 and of the Tyr residues 20 and 27 is probably due to their role in stabilizing the hairpin-like structure of the hormone by means of a hydrophobic core [46]. Kirby and coworkers performed a d-amino acid scan of NPY that showed an affinity profile very similar to that of the l-Ala scan [47].…”

Neuropeptide Y and Epilepsy

“…Our laboratory recently tested this question by using a newly developed antagonist to the Y 2 receptor, BIIE 0246 (50), which profoundly reduced the presynaptic response to NPY and to the selective Y 2 -receptor agonist, [ahx [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] ]NPY (51). Indeed, 30 n M BIIE 0246 reduced the effect of NPY in area CA1 of hippocampal slices to 40% of control levels (52; Fig.…”

Structurally conserved C-RFa revealed prolactin releasing activity in vitro and gene expression changes in pituitary of seasonally acclimatized carp

“…Structural similarity was also observed between h-PrRP20 and neuropeptide Y, NPY (D'Ursi et al 2002). Arg19 in C-RFa corresponds to Arg35 in NPY, which has been reported to be crucial for NPY activity since its single replacement by Ala leads to a complete loss of affi nity for all cloned NPY receptor subtypes (Cabrele and Beck-Sickinger 2000). In the N-terminal region of the proposed model for the C-RFa peptide, a tendency to form a β-turn structure is predicted which includes two highly conserved proline residues (Pro2 and Pro6, Fig.…”