Conformation of parathyroid hormone antagonists by CD, NMR, and molecular dynamics simulations
Abstract
The conformation of two highly potent parathyroid hormone (PTH) antagonists was investigated in water/2,2,2-trifluoroethanol mixtures. The two peptides are derived from the sequence (7-34) of PTH and of PTH-related protein (PTHrP) and have a D-Trp replacing Gly in position 12. In the analogue derived from PTHrP, Lys11 was replaced by Leu to remove the residual agonist activity. The study was conducted by CD and two-dimensional proton magnetic resonance spectroscopy, and the nuclear Overhauser effects found were utilized in restrained distance geometry and molecular dynamics simulations. Both peptides adopt a helical C-terminal conformation, which seems more stable in the case of the PTHrP analogue. A type II' beta-turn centered around D-Trp12 and Lys13 is present in both structures.
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