The PP-fold solution structure of human polypeptide YY and human PYY3-36 as determined by NMR.
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.
Nygaard
Rie
R
Structural Biology and NMR Laboratory, Institute of Molecular Biology and Physiology, University of Copenhagen, Øster Farimagsgade 2A, DK-1353 Copenhagen K, Denmark.
Nielbo
Steen
S
Schwartz
Thue W
TW
Poulsen
Flemming M
FM
D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006801:Humans; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments; D019894:Peptide YY / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D017510:Protein Folding; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism; D012996:Solutions / Q000737:chemistry; D014162:Transfection
D010446:Peptide Fragments; D011964:Receptors, Gastrointestinal Hormone; D012996:Solutions; D019894:Peptide YY; C061785:peptide YY (3-36)