Structural features of parathyroid hormone receptor coupled to Galpha(s)-protein.

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 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.

journal_name

Biophys J

journal_title

Biophysical journal

authors

Plati J,Tsomaia N,Piserchio A,Mierke DF

doi

10.1529/biophysj.106.094813

subject

Has Abstract

pub_date

2007-01-15 00:00:00

pages

535-40

issue

2

eissn

0006-3495

issn

1542-0086

pii

S0006-3495(07)70853-6

journal_volume

92

pub_type

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