Three-dimensional solution structure of a disulfide bond isomer of the human insulin-like growth factor-I.
The solution structure of a disulfide bond isomer of human insulin-like growth factor-I (IGF-I) was determined using homonuclear NMR methods. A total of 292 interatomic distance constraints, including 12 related to the disulfide bridges, was used in the distance geometry calculations. The determined structures contain two helical rods corresponding to the sequence regions, Ala8-Cys18 and Leu54-Cys61. Comparison with the previously determined structure of native human IGF-I revealed partial correspondence of the secondary structure (helices I: Ala8-Cys18 and helices III: Leu54-Cys61) and internal packing. Helix II in native human IGF-I (residues Gly42-Cys48) is disrupted in the isomer. A similar relationship has been described between the structure of native insulin and a homologous disulfide isomer, suggesting that these alternative folds represent general features of insulin-like sequences. In each case the precision of the distance geometry ensemble is low due in part to resonance broadening and a paucity of NOEs relative to other globular proteins of this size. These observations suggest that tertiary structure of the isomer is not highly ordered. Comparison of the biological activities of native and the disulfide bond isomer of human IGF-I highlight the importance of Tyr24, Phe25, Phe49-Cys52 and Phe16 in binding to the IGF-I receptor or specific IGFBPs. The relationship of this proposed receptor-binding surface of human IGF-I to those of insulin is discussed.
Sato
A
A
Research Laboratories, Fujisawa Pharmaceutical Co., Ltd, Osaka, Japan. akihiro_sato@po.fujisawa.co.jp
Koyama
S
S
Yamada
H
H
Suzuki
S
S
Tamura
K
K
Kobayashi
M
M
Niwa
M
M
Yasuda
T
T
Kyogoku
Y
Y
Kobayashi
Y
Y
D000595:Amino Acid Sequence; D003903:Deuterium; D004220:Disulfides / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000737:chemistry; D018969:Insulin-Like Growth Factor Binding Proteins / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000737:chemistry* / Q000378:metabolism*; D007536:Isomerism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017526:Receptor, IGF Type 1 / Q000378:metabolism
D004220:Disulfides; D007328:Insulin; D018969:Insulin-Like Growth Factor Binding Proteins; D007334:Insulin-Like Growth Factor I; D003903:Deuterium; D017526:Receptor, IGF Type 1