The conformational and biological analysis of a cyclic anti-obesity peptide from the C-terminal domain of human growth hormone.
The three-dimensional solution structure of antiobesity drug (AOD), a 15-residue, disulfide-bonded, cyclic peptide, cyclo(6,13)-H2N-Leu-Arg-Ile-Val-Gln-Cys-Arg-Ser-Val-Glu-Gly-Ser-Cys-Gly-Phe-OH, derived from the C-terminal domain of the human growth hormone (hGH) (residues 177-191) was determined using two-dimensional 1H NMR spectroscopy. AOD stimulates lipolysis and inhibits lipogenesis, in vitro, in rodent, porcine and human adipose tissues. These biological effects suggest that AOD is a potential therapeutic candidate for the treatment of obesity. Conformational studies of AOD were conducted in aqueous solution and in water/dimethylsulfoxide mixtures. In general, spectral quality was superior in the water/ dimethylsulfoxide mixtures. The cyclic region of AOD in water/dimethylsulfoxide adopts type I beta-turns at residues Ser8-Val9-Glu10-Gly11 and Ser12-Cys13-Gly14-Phe15, each preceded by loop-like structures. Comparison of the conformation of this peptide with residues 177-191 in the native hGH protein X-ray crystal structure indicates that the synthetic peptide retains some structural similarity to the intact protein. This study provides evidence that the C-terminal region of hGH is a specific functional domain of the multifunctional hGH protein.
Ogru
E
E
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Monash University, Clayton, Australia.
Wilson
J C
JC
Heffernan
M
M
Jiang
W J
WJ
Chalmers
D K
DK
Libinaki
R
R
Ng
F
F
D000273:Adipose Tissue / Q000737:chemistry; D000409:Alanine / Q000737:chemistry; D000595:Amino Acid Sequence; D000818:Animals; D018360:Crystallography, X-Ray; D019382:Human Growth Hormone / Q000737:chemistry* / Q000502:physiology*; D006801:Humans; D008066:Lipolysis; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010452:Peptide Biosynthesis; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D013552:Swine
D010455:Peptides; D019382:Human Growth Hormone; D000409:Alanine