Conformation-activity relationship of neuropeptide S and some structural mutants: helicity affects their interaction with the receptor.
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.
Tancredi
Teodorico
T
Istituto di Chimica Biomolecolare, CNR, Via Campi Flegrei 34, I-80078 Pozzuoli, Italy.
Guerrini
Remo
R
Marzola
Erika
E
Trapella
Claudio
C
Calo
Girolamo
G
Regoli
Domenico
D
Reinscheid
Rainer K
RK
Camarda
Valeria
V
Salvadori
Severo
S
Temussi
Piero Andrea
PA
D000595:Amino Acid Sequence; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009479:Neuropeptides / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018013:Receptors, Neuropeptide / Q000819:agonists; D011994:Recombinant Proteins / Q000819:agonists; D012996:Solutions; D013329:Structure-Activity Relationship
D009479:Neuropeptides; D018013:Receptors, Neuropeptide; D011994:Recombinant Proteins; D012996:Solutions; C506531:neuropeptide S, human; D002118:Calcium