Parathyroid hormone-related protein plays a major role in the pathogenesis of humoral hypercalcemia of malignancy. Under normal physiological conditions, parathyroid hormone-related protein is produced in a wide variety of tissues and acts in an autocrine or paracrine fashion. Parathyroid hormone-related protein and parathyroid hormone bind to and activate the same G-protein-coupled receptor. Here we present the structure of the biologically active NH P -terminal domain of human parathyroid hormone-related protein(1^34) in nearphysiological solution in the absence of crowding reagents as determined by two-dimensional proton magnetic resonance spectroscopy. An improved strategy for structure calculation revealed the presence of two helices, His-5^Leu-8 and Gln-16L eu-27, connected by a flexible linker. The parathyroid hormone-related protein(1^34) structure and the structure of human parathyroid hormone(1^37) as well as human parathyroid hormone(1^34) are highly similar, except for the well defined turn, His-14^Ser-17, present in parathyroid hormone. Thus, the similarity of the binding affinities of parathyroid hormone and parathyroid hormone-related protein to their common receptor may be based on their structural similarity.z 1999 Federation of European Biochemical Societies.