Addressing the tertiary structure of human parathyroid hormone-(1-34).
Parathyroid hormone (PTH) regulates mineral metabolism and bone turnover by activating specific receptors located on osteoblastic and renal tubular cells and is fully functional as the N-terminal 1-34 fragment, PTH-(1-34). Previously, a "U-shaped" conformation with N- and C-terminal helices brought in close proximity by a turn has been postulated. The general acceptance of this hypothesis, despite limited experimental evidence, has altered the direction of the design of PTH-analogs. Examining the structure of human PTH-(1-34) under conditions that encompass the different environments the hormone may experience in the approach to and interaction with the G-protein-coupled receptor (including benign aqueous and saline solutions and in the presence of dodecylphosphocholine), we observe no evidence for a U-shape conformation or any tertiary structure. Instead, the N- and C-terminal helical domains, which vary in length and stability depending on the conditions, are separated by a highly flexible region of undefined conformation. These observations are in complete accord with recent conformational studies of PTH-related protein analogs containing lactams (Mierke, D. F., Maretto, S., Schievano, E. , DeLuca, D., Bisello, A., Mammi, S., Rosenblatt, M., Peggion, E., and Chorev, M. (1997) Biochemistry 36, 10372-10383) or a model amphiphilic alpha-helix (Pellegrini, M., Bisello, A., Rosenblatt, M., Chorev, M., and Mierke, D. F. (1997) J. Med. Chem. 40, 3025-3031). Reliable structural data from different environmental conditions are absolutely requisite for the next step in the design of non-peptide PTH analogs.
Pellegrini
M
M
Gustaf H. Carlson School of Chemistry, Clark University, Worcester, Massachusetts 01610, USA.
Royo
M
M
Rosenblatt
M
M
Chorev
M
M
Mierke
D F
DF
D002942:Circular Dichroism; D015195:Drug Design; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D018716:Molecular Mimicry; D017434:Protein Structure, Tertiary; D019379:Teriparatide / Q000819:agonists / Q000737:chemistry*
D019379:Teriparatide