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Arginine 186 in the Extracellular N-Terminal Region of the Human Parathyroid Hormone 1 Receptor Is Essential for Contact with Position 13 of the Hormone

Division of Bone and Mineral Metabolism Charles A. Dana and Thorndike Laboratories Department of Medicine Beth Israel Deaconess Medical Center and Harvard Medical School Boston, Massachusetts 02215

PTH maintains blood calcium concentrations within the physiological range by acting on a G protein-coupled heptahelical receptor (PTH1 Rc) located primarily in cells in bone and kidney. We have undertaken a photoaffinity cross-linking approach to elucidate the nature of the bimolecular interaction of PTH with the human (h) PTH1 Rc. Specifically, we have studied the region of the receptor that interacts with the midregion of PTH-(1–34), position 13, using a benzophenone-containing photoaffinity ligand, ¹²⁵I-[Nle^8,18,Lys¹³(-pBz₂),L-2-Nal²³,Arg^26,27,Tyr³⁴]bPTH-(1–34)NH₂ (¹²⁵I-K13). Using site-directed mutagenesis in combination with biochemical analysis, we have reduced our previously identified contact domain, 17 residues in the extracellular region of the receptor (173–189), to an 8-amino acid domain (182–189). Furthermore, we have found arginine 186 to be of critical importance to the interaction of the hPTH1 Rc with ¹²⁵I-K13: modification of Arg¹⁸⁶ to either lysine or alanine does not modify receptor avidity or signal transduction by the receptor, but eliminates cross-linking to ¹²⁵I-K13.

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