title: Analogs of pancreatic polypeptide and peptide YY with a locked PP-fold structure are biologically active.
abstract: Pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY), members of the PP-fold family share a high degree of sequence homology. Nuclear magnetic resonance (NMR) and X-ray crystallography studies have shown these peptides can adopt a tightly organized tertiary structure called the PP-fold, which has long been assumed to be the active structure of this family of peptides. To date, however, no studies have been completed with PYY and PP which confirm if the PP-fold structure is important for their physiological actions. The aim of the study was to test if PYY and PP locked into the PP-fold maintained biological activity. Therefore, we designed and produced analogs of PP and PYY in a cyclic conformation with two cysteine amino acid substitutions at the N-terminus and at position 27. These were oxidized to form a cysteine disulfide bond locking the peptides into the PP-fold structure. Studies demonstrate that the cyclic analogs have both similar in vivo activity to their parent molecules, and affinity for the Y2 and Y4 receptors. Results suggest that the proposed PP and PYY-fold is likely to be their biologically active conformation.
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Imperial College, London, UK.
authors.forename: Natacha
authors.initials: N
authors.lastname: Germain
authors.forename: James S
authors.initials: JS
authors.lastname: Minnion
authors.forename: Tricia
authors.initials: T
authors.lastname: Tan
authors.forename: Joyceline
authors.initials: J
authors.lastname: Shillito
authors.forename: Clare
authors.initials: C
authors.lastname: Gibbard
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ghatei
authors.forename: Stephen
authors.initials: S
authors.lastname: Bloom
mesh_terms: D000818:Animals; D003553:Cystine / Q000138:chemical synthesis / Q000737:chemistry*; D004435:Eating / Q000187:drug effects*; D005508:Food Deprivation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010191:Pancreatic Polypeptide / Q000737:chemistry* / Q000494:pharmacology; D019894:Peptide YY / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017476:Receptors, Neuropeptide Y / Q000737:chemistry
chemical_list: D010456:Peptides, Cyclic; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; D019894:Peptide YY; D003553:Cystine; C109491:neuropeptide Y4 receptor; D010191:Pancreatic Polypeptide