The structure of human parathyroid hormone‐related protein(1–34) in near‐physiological solution

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Abstract
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 NH2‐terminal domain of human parathyroid hormone‐related protein(1–34) in near‐physiological 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‐16–Leu‐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.