Conformationally restricted PACAP27 analogues incorporating type II/II' IBTM beta-turn mimetics. Synthesis, NMR structure determination, and binding affinity.
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.
González-Muñiz
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R
Instituto de Química Médica (CSIC), Juan de la Cierva 3, 28006 Madrid, Spain. iqmg313@iqm.csic.es
Martín-Martínez
M
M
Granata
C
C
de Oliveira
E
E
Santiveri
C M
CM
González
C
C
Frechilla
D
D
Herranz
R
R
García-López
M T
MT
Del Río
J
J
Angeles Jiménez
M
M
Andreu
D
D
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
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