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

Parathyroid hormone-related protein plays a major role in the pathogenesis of humoral hypercalcemia of malignancy. Under normal physiological conditio ns, parathyroid hormone-related protein is produced in a wide variety of ti ssues and acts in an autocrine or paracrine fashion. Parathyroid hormone-re lated protein and parathyroid hormone bind to and activate the same G-prote in-coupled receptor. Here we present the structure of the biologically acti ve NH2-terminal domain of human parathyroid hormone-related protein(1-34) i n near-physiological solution in the absence of crowding reagents as determ ined by two-dimensional proton magnetic resonance spectroscopy. An improved strategy for structure calculation revealed the presence of two helices, H is-5-Leu-8 and Gln-16-Leu-27, connected by a flexible linker. The parathyro id hormone-related protein(1-34) structure and the structure of human parat hyroid 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 parath yroid hormone. Thus, the similarity of the binding affinities of parathyroi d hormone and parathyroid hormone-related protein to their common receptor may be based on their structural similarity. (C) 1999 Federation of Europea n Biochemical Societies.