Structural features of parathyroid hormone receptor coupled to Galpha(s)-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 Galpha(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 Galpha(s) activation by PTH1R, the structure of this region, PTH1R(402-408), while bound to Galpha(s), was determined by transferred nuclear Overhauser effect spectroscopy. The relative topological orientation of the IC3 while associated with Galpha(s) was determined by saturation transfer difference spectroscopy. These experimental data were incorporated into molecular dynamics simulations of the PTH1R and Galpha(s) to provide atomic insight into the receptor-protein interactions important for PTH signaling and a structural framework to analyze previous mutagenesis studies of Galpha(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.
Plati
Jessica
J
Department of Chemistry, and Department of Molecular Pharmacology, Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912, USA.
Tsomaia
Natia
N
Piserchio
Andrea
A
Mierke
Dale F
DF
D001665:Binding Sites; D003198:Computer Simulation; D044385:GTP-Binding Protein alpha Subunits / Q000737:chemistry* / Q000648:ultrastructure*; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000737:chemistry* / Q000648:ultrastructure*; D013329:Structure-Activity Relationship
D044385:GTP-Binding Protein alpha Subunits; D044168:Receptor, Parathyroid Hormone, Type 1