STRUCTURE-ACTIVITY RELATION OF NH2-TERMINAL HUMAN PARATHYROID-HORMONEFRAGMENTS

Human parathyroid hormone (hPTH) is involved in the regulation of the calcium level in blood. This hormone function is located in the NH2-te rminal 34 amino acids of the 84-amino acid peptide hormone and is tran sduced via the adenylate cyclase and the phosphatidylinositol signalin g pathways. it is well known that truncation of the two NH2-terminal a mino acids of the hormone leads to complete loss of in vivo normocalce mic function. To correlate loss of calcium level regulatory activity a fter stepwise NH2-terminal truncation and solution structure, we studi ed the conformations of fragments hPTH-(2-37), hPTH-(3-37), and hPTH-( 4-37) in comparison to hPTH-(1-37) in aqueous buffer solution under ne ar physiological conditions by circular dichroism spectroscopy, two-di mensional nuclear magnetic resonance spectroscopy, and restrained mole cular dynamics calculations, All peptides show helical structures and hydrophobic interactions between Leu-15 and Trp-23 that lead to a defi ned loop region from His-14 to Ser-17. A COOH-terminal helix from Met- 18 to at least Leu-28 was found for all peptides. The helical structur e in the NH2-terminal part of the peptides was lost in parallel with t he NH2-terminal truncation and can be correlated with the loss of calc ium regulatory activity.