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 gro wth factor-I (IGF-I) was determined using homonuclear NMR methods. A total of 292 interatomic distance constraints, including 12 related to the disulf ide bridges, was used in the distance geometry calculations The determined structures contain two helical rods corresponding to the sequence regions, Ala(8)-Cys(18) and Leu(54)-Cys(61). Comparison with the previously determin ed structure of native human ICF-I revealed partial correspondence of the s econdary structure (helices I: Ala(8)-Cys(18) and helices III: Leu(54)-Cys( 61)) and internal packing. Helix II in native human IGF-I (residues Gly(42) -Cys(48)) is disrupted in the isomer. A similar relationship has been descr ibed between the structure of native insulin and a homologous disulfide iso mer, suggesting that these alternative folds represent general features of insulin-like sequences. In each case the precision of the distance geometry ensemble is tow due in part to resonance broadening and a paucity of NOEs relative to other globular proteins of this size. These observations sugges t that tertiary structure of the isomer is not highly ordered. Comparison o f the biological activities of native and the disulfide bond isomer of huma n IGF-I highlight the importance of Tyr(24), Phe(25), Phe(49-)Cys(52) and P he(16) in binding to the IGF-I receptor or specific IGFBPs. The relationshi p of this proposed receptor-binding surface of human IGF-I to those of insu lin is discussed.