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Article

The PP-Fold Solution Structure of Human Polypeptide YY and Human PYY3-36 As Determined by NMR^†^,^‡

Supporting Info

Rie Nygaard,^§ Steen Nielbo,^§ Thue W. Schwartz, and Flemming M. Poulsen*^§

Structural Biology and NMR Laboratory, Institute of Molecular Biology and Physiology, University of Copenhagen, ster Farimagsgade 2A, DK-1353 Copenhagen K, Denmark, Laboratory for Molecular Pharmacology, Department of Pharmacology, The Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark, and 7TM Pharma A/S Hrsholm, Denmark

Biochemistry, 2006, 45 (27), pp 8350–8357

DOI: 10.1021/bi060359l

Publication Date (Web): June 16, 2006

†

We thank “The John and Birthe Meyer Foundation” for the donation to establish the SBiN-Lab, and “The Biocampus Program of The University of Copenhagen” for a scholarship to Rie Nygaard.

‡

Coordinates have been deposited in the Protein Data Bank (PDB entries: 2DF0 and 2DEZ).

Institute of Molecular Biology and Physiology, University of Copenhagen.

The Panum Institute, University of Copenhagen.

7TM Pharma A/S.

Corresponding author: Flemming M. Poulsen, Structural Biology and NMR Laboratory, Institute of Molecular Biology, University of Copenhagen, Øster Farimagsgade 2A, DK-1353 Copenhagen K. E-mail, fmp@apk.molbio.ku.dk; phone, +45 3532 2077; fax, +45 3532 2075.

Abstract

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.

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