NMR SOLUTION STRUCTURE OF THE [ALA(26)]PARATHYROID-HORMONE-RELATED PROTEIN(1-34) EXPRESSED IN HUMORAL HYPERCALCEMIA OF MALIGNANCY

The structure of the biologically active N-terminal domain of human parathyroid-hormone-related protein (residues 1 - 34) containing an Ala substituted for a His in position 26 was studied by two-dimensional proton NMR spectroscopy. Unambiguous NMR assignments of all backbone and side-chain hydrogens were made with the aid of totally correlated spectroscopy experiments, which provided through-bond H-1-H-1 connectivities, and NOE spectroscopy, which provided through-space and sequential backbone connectivities. The NMR data were utilized in distance-geometry algorithms to generate a family of structures. The major structural features include two segments of alpha-helix extending from Glu4 to Lys13 and from Leu27 to Thr33, with two turns from Gln16 to Arg19 and Phe22 to His25. A salt-bridge appears likely between Arg20 and Glu30 which may be critical for holding the receptor-binding domain together.