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Structural Features of Parathyroid Hormone Receptor Coupled to G_S-Protein

Jessica Plati ^*, Natia Tsomaia , Andrea Piserchio  and Dale F. Mierke ^* 

^* Department of Chemistry, and Department of Molecular Pharmacology, Division of Biology & Medicine, Brown University, Providence, Rhode Island

Correspondence: Address reprint requests to Dale F. Mierke, Dept. of Molecular Pharmacology, Div. of Biology & Medicine, Box G-B4, Brown University, Providence, RI 02912. Tel.: 401-863-2139; Fax: 401-863-1595; E-mail: dale_mierke{at}brown.edu.

The molecular basis of the activation of G-proteins by the G-protein coupled receptor for parathyroid hormone (PTH) is unknown. Employing a combination of NMR methods and computer-based structural refinement, structural features involved in the activation of G_s by the PTH receptor (PTH1R) have been determined. Focusing on the C-terminus of the third intracellular loop (IC3), previously shown to be important for G_s activation by PTH1R, the structure of this region, PTH1R(402–408), while bound to G_s, was determined by transferred nuclear Overhauser effect spectroscopy. The relative topological orientation of the IC3 while associated with G_s was determined by saturation transfer difference spectroscopy. These experimental data were incorporated into molecular dynamics simulations of the PTH1R and G_s to provide atomic insight into the receptor-protein interactions important for PTH signaling and a structural framework to analyze previous mutagenesis studies of G_s. These data provide the first step toward development of a molecular mechanism for the signaling profile of PTH1R, an important regulator of calcium levels in the bloodstream.