Structural Features of Parathyroid Hormone Receptor Coupled to GαS-Protein

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 Gαs 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 Gαs activation by PTH1R, the structure of this region, PTH1R(402–408), while bound to Gαs, was determined by transferred nuclear Overhauser effect spectroscopy. The relative topological orientation of the IC3 while associated with Gαs was determined by saturation transfer difference spectroscopy. These experimental data were incorporated into molecular dynamics simulations of the PTH1R and Gαs to provide atomic insight into the receptor-protein interactions important for PTH signaling and a structural framework to analyze previous mutagenesis studies of Gαs. 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.