title: Conformationally restricted PACAP27 analogues incorporating type II/II' IBTM beta-turn mimetics. Synthesis, NMR structure determination, and binding affinity.
abstract: To probe the importance of a proposed beta-turn within residues S9-R12 of PACAP for recognition by VIP/PACAP receptors, compounds 1 and 2, two conformationally restricted analogues of PACAP27 incorporating respectively (S)- or (R)-IBTM as type II or II' beta-turn dipeptide mimetic at the Y10-S11 position, were synthesized. According to 1H NMR conformational analyses in aqueous solution and 30% TFE, both PACAP27 and the [S-IBTM(10,11)]PACAP27 analogue 1 adopt similar ordered structures. PACAP27 shows an N-terminal disordered region (residues H1-F6) and an alpha-helical conformation within segment T7-L27. For residues S9-R12, our data seem more compatible with a segment of the alpha-helix than with the beta-turn previously proposed for this fragment. In compound 1 the alpha-helix, also spanning T7-L27 residues, appears slightly distorted at the N-terminus relative to the native peptide. Although this distortion could lead to the marked decrease in binding affinity of this compound at the VIP/PACAP receptors, the lack of the Y10 side chain in analogues 1 and 2 could also significantly affect the binding of these compounds.
authors.affiliation: Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain. iqmg313@iqm.csic.es
authors.forename: R
authors.initials: R
authors.lastname: González-Muñiz
authors.forename: M
authors.initials: M
authors.lastname: Martín-Martínez
authors.forename: C
authors.initials: C
authors.lastname: Granata
authors.forename: E
authors.initials: E
authors.lastname: de Oliveira
authors.forename: C M
authors.initials: CM
authors.lastname: Santiveri
authors.forename: C
authors.initials: C
authors.lastname: González
authors.forename: D
authors.initials: D
authors.lastname: Frechilla
authors.forename: R
authors.initials: R
authors.lastname: Herranz
authors.forename: M T
authors.initials: MT
authors.lastname: García-López
authors.forename: J
authors.initials: J
authors.lastname: Del Río
authors.forename: M
authors.initials: M
authors.lastname: Angeles Jiménez
authors.forename: D
authors.initials: D
authors.lastname: Andreu
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D007211:Indoles / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009479:Neuropeptides / Q000737:chemistry* / Q000378:metabolism*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D018005:Receptors, Vasoactive Intestinal Peptide / Q000378:metabolism*; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D013329:Structure-Activity Relationship
chemical_list: C495403:Adcyap1 protein, rat; D007211:Indoles; D009479:Neuropeptides; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D018005:Receptors, Vasoactive Intestinal Peptide; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; C448863:S-IBTM