The PP-fold solution structure of human polypeptide YY and human PYY3-36 as determined by NMR

TY - JOUR

T1 - The PP-fold solution structure of human polypeptide YY and human PYY3-36 as determined by NMR

AU - Nygaard, Rie

AU - Nielbo, Steen

AU - Schwartz, Thue W

AU - Poulsen, Flemming M

N1 - Keywords: Amino Acid Sequence; Animals; COS Cells; Cercopithecus aethiops; Humans; Molecular Sequence Data; Nuclear Magnetic Resonance, Biomolecular; Peptide YY; Protein Conformation; Protein Folding; Receptors, Gastrointestinal Hormone; Solutions; Transfection

PY - 2006

Y1 - 2006

N2 - PYY3-36 is a biopharmaceutical antiobesity agent under development as well as an endogenous satiety hormone, which is generated by dipeptidyl peptidase-IV digestion of polypetide YY (PYY), and in contrast to the parent hormone, PYY is highly selective for the Y2 versus the Y1 receptor. NMR analysis revealed a highly ordered, back-folded structure for human PYY in aqueous solution similar to the classical PP-fold structure of pancreatic polypeptide. The NMR analysis of PYY3-36 also showed a folded structure resembling a PP-fold, which however was characterized by far fewer long distance NOEs than the PP-fold observed in the full-length peptide. This suggests that either a conformational change has occurred in the N-terminal segment of PYY3-36 or that this segments is characterized by larger dynamics. The study supports the notion that the PP-fold is crucial for establishing simultaneous interactions with two subsites in the receptor for binding of, respectively, the N- and C-terminal ends of PYY. The Y2 receptor only requires recognition of the C-terminal segment of the molecule as displayed by the Y2 selective PYY3-36.

AB - PYY3-36 is a biopharmaceutical antiobesity agent under development as well as an endogenous satiety hormone, which is generated by dipeptidyl peptidase-IV digestion of polypetide YY (PYY), and in contrast to the parent hormone, PYY is highly selective for the Y2 versus the Y1 receptor. NMR analysis revealed a highly ordered, back-folded structure for human PYY in aqueous solution similar to the classical PP-fold structure of pancreatic polypeptide. The NMR analysis of PYY3-36 also showed a folded structure resembling a PP-fold, which however was characterized by far fewer long distance NOEs than the PP-fold observed in the full-length peptide. This suggests that either a conformational change has occurred in the N-terminal segment of PYY3-36 or that this segments is characterized by larger dynamics. The study supports the notion that the PP-fold is crucial for establishing simultaneous interactions with two subsites in the receptor for binding of, respectively, the N- and C-terminal ends of PYY. The Y2 receptor only requires recognition of the C-terminal segment of the molecule as displayed by the Y2 selective PYY3-36.

U2 - 10.1021/bi060359l

DO - 10.1021/bi060359l

M3 - Journal article

C2 - 16819834

SN - 0006-2960

VL - 45

SP - 8350

EP - 8357

JO - Biochemistry

JF - Biochemistry

IS - 27

ER -