Protein Structure and Folding
Structural Basis for Antibody Discrimination between Two Hormones That Recognize the Parathyroid Hormone Receptor*

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Parathyroid hormone-related protein (PTHrP) plays a vital role in the embryonic development of the skeleton and other tissues. When it is produced in excess by cancers it can cause hypercalcemia, and its local production by breast cancer cells has been implicated in the pathogenesis of bone metastasis formation in that disease. Antibodies have been developed that neutralize the action of PTHrP through its receptor, parathyroid hormone receptor 1, without influencing parathyroid hormone action through the same receptor. Such neutralizing antibodies against PTHrP are therapeutically effective in animal models of the humoral hypercalcemia of malignancy and of bone metastasis formation. We have determined the crystal structure of the complex between PTHrP (residues 1–108) and a neutralizing monoclonal anti-PTHrP antibody that reveals the only point of contact is an α-helical structure extending from residues 14–29. Another striking feature is that the same residues that interact with the antibody also interact with parathyroid hormone receptor 1, showing that the antibody and the receptor binding site on the hormone closely overlap. The structure explains how the antibody discriminates between the two hormones and provides information that could be used in the development of novel agonists and antagonists of their common receptor.

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The atomic coordinates and structure factors (code 3FFD) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

*

This work was supported in part by grants from the Cancer Council of Victoria and National Health and Medical Research Council of Australia with infrastructural support from the Australian Cancer Research Foundation Rational Drug Discovery Facility. This work, including use of the BioCARS sector, was also supported by the Australian Synchrotron Research Program, which is funded by the Commonwealth of Australia. Use of the Advanced Photon Source was supported by the United States Department of Energy, Basic Energy Sciences, Office of Energy Research.

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J. A. Barden, unpublished results.

1

Both authors contributed equally to this work.

2

A National Health and Medical Research Council of Australia Industry Fellow. Present address: Commonwealth Scientific and Industrial Research Organization Molecular and Health Technologies, Parkville, Victoria 3052, Australia.

3

A National Health and Medical Research Council of Australia RD WrightFellow.

4

A National Health and Medical Research Council of Australia Principal Research Fellow. Present address: Prince Henry's Institute, Clayton, Victoria 3168, Australia.