Designing analogues of mini atrial natriuretic peptide based on structural analysis by NMR and restrained molecular dynamics.
Analogues of mini atrial natriuretic peptide (miniANP) that provide conformational properties related to biological activity were designed on the basis of the structure revealed by NMR and restrained molecular dynamics (rMD) simulation, and an analogue with a high level of biological activity was successfully obtained. MiniANP is a cyclic pentadecapeptide analogue of atrial natriuretic polypeptide (ANP). The conformation of miniANP analyzed by NMR and rMD simulation indicated that positive phi angles are preferred for Gly(5) and Gly(6), which is typical for D-amino acids. On the basis of the structural information, [D-Ala(5)]miniANP, [D-Ala(6)]miniANP, and [D-Ala(5) D-Ala(6)]miniANP were synthesized. The biological activity of [D-Ala(5)]miniANP was stronger than that of miniANP, confirming that Gly(5) of miniANP takes a positive phi angle on binding to the receptor. Conformational analysis of these analogue peptides by NMR suggested that a turnlike conformation at residues 6-9 and a proximate pair formed by side chains of Phe(4) and Ile(11) are important for the biological activity.
Sugase
Kenji
K
Suntory Institute for Bioorganic Research and Suntory Institute for Biomedical Research, Shimamoto, Mishima 618-8503, Japan.
Oyama
Yoshiaki
Y
Kitano
Katsuhiko
K
Iwashita
Takashi
T
Fujiwara
Toshimichi
T
Akutsu
Hideo
H
Ishiguro
Masaji
M
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000737:chemistry*; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D012996:Solutions
D009842:Oligopeptides; D010456:Peptides, Cyclic; D012996:Solutions; D009320:Atrial Natriuretic Factor; D000242:Cyclic AMP