Neuropeptide S (NPS) is the endogenous ligand of the previously orphan G-protein coupled receptor now named NPSR. The NPS-NPSR receptor system regulates important biological functions such as sleep/ waking, locomotion, anxiety and food intake. Recently, exhaustive Ala scan and D-amino acid scan studies, together with systematic N- and C-terminal truncation, led to the identification of key residues for biological activity. Because conformational preferences might also play an important role, we undertook a detailed conformational analysis of NPS and several analogues in solution. We show that helicity induced by substitution of three flexible residues in the 5-13 regulatory region abolishes biological activity. A parallel pharmacological and conformational study of single and multiple substitutions of glycines 5, 7, and 9 showed that helicity can be tolerated in the C-terminal part of the peptide but not around Gly7. The identification of hNPSR partial agonists heralds the possibility of designing pure NPS receptor antagonists.

Conformation-activity relationship of neuropeptide S and some structural mutants: Helicity affects their interaction with the receptor

GUERRINI, Remo;MARZOLA, Erika;TRAPELLA, Claudio;CALO', Girolamo;REGOLI, Domenico;CAMARDA, Valeria;SALVADORI, Severo;
2007

Abstract

Neuropeptide S (NPS) is the endogenous ligand of the previously orphan G-protein coupled receptor now named NPSR. The NPS-NPSR receptor system regulates important biological functions such as sleep/ waking, locomotion, anxiety and food intake. Recently, exhaustive Ala scan and D-amino acid scan studies, together with systematic N- and C-terminal truncation, led to the identification of key residues for biological activity. Because conformational preferences might also play an important role, we undertook a detailed conformational analysis of NPS and several analogues in solution. We show that helicity induced by substitution of three flexible residues in the 5-13 regulatory region abolishes biological activity. A parallel pharmacological and conformational study of single and multiple substitutions of glycines 5, 7, and 9 showed that helicity can be tolerated in the C-terminal part of the peptide but not around Gly7. The identification of hNPSR partial agonists heralds the possibility of designing pure NPS receptor antagonists.
2007
Tancredi, T; Guerrini, Remo; Marzola, Erika; Trapella, Claudio; Calo', Girolamo; Regoli, Domenico; Reinscheid, Rk; Camarda, Valeria; Salvadori, Severo...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/470750
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