STRUCTURAL FEATURES OF PARATHYROID HORMONE RECEPTOR COUPLED TO G_s-PROTEIN

¹ Brown University

^* To whom correspondence should be addressed. E-mail: dale_mierke{at}brown.edu.

Submitted on August 4, 2006
Revised on September 6, 2006
Accepted on 12 September 2006

	Abstract

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 Gs 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 towards development of a molecular mechanism for the signaling profile of PTH1R, an important regulator of calcium levels in the bloodstream.

Key Words: NMR, Parathyroid Hormone, calcium metastasis, g protein coupled receptors, signal transduction, structure