NMR solution structure of human parathyroid hormone(1-34).

The aqueous solution structure of the biologically-active N-terminal domain of human parathyroid hormone (residues 1-34) was studied by two-dimensional proton nuclear magnetic resonance (2D NMR) spectroscopy, distance geometry, and dynamic simulated annealing. Unambiguous NMR assignments of all backbone and side chain hydrogens were made with the aid of totally correlated spectroscopy experiments, which provided through-bond 1H-1H connectivities, and nuclear Overhauser effect spectroscopy, which provided through-space and sequential backbone connectivities. The NMR data acquired were utilized in a distance geometry algorithm to generate a family of structures which were then refined using dynamic simulated annealing. The major structural feature evident is alpha-helix extending from residues Glu4 to Lys13 and from Val21 to Gln29 with a turn incorporating Asn16-Glu19 resulting in a quite globular C-terminal domain with a hydrophobic core comprising Leu15, Leu18, Trp23, and Val31. Structure-activity studies are interpreted in terms of the deduced conformation of the PTH structure with particular reference to the likely PTH receptor binding site formed primarily by the bulk of the C-terminal helix.