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Proteins. 2014 Jul;82(7):1370-5. doi: 10.1002/prot.24503. Epub 2014 Jan 15.

Engineering a soluble parathyroid hormone GPCR mimetic.

Author information

1
Department of Chemistry, Dartmouth College, Hanover, New Hampshire, 03755.

Abstract

We designed and characterized a soluble mimic of the parathyroid hormone (PTH) receptor (PTH1R) that incorporates the N-terminus and third extracellular loop of PTH1R, important for ligand binding. The engineered receptor (PTH1R-NE3) was conceived to enable easy production and the use of standard biochemical and biophysical assays for the screening of competitive antagonists of PTH. We show that PTH1R-NE3 is folded, thermodynamically stable and selectively binds PTH. We also demonstrate the utility of our mimic by identifying a small molecule that competes with PTH in our PTH1R-NE3-based fluorescence polarization assay. Antagonists to PTH1R, a transmembrane protein belonging to the class B G-protein coupled receptor family, may provide new therapeutic options for calcium metabolism diseases like humoral hypercalcemia of malignancy.

KEYWORDS:

GPCR; NMR; drug development; drug screening; fluorescence polarization; photoaffinity crosslinking; receptor mimetic

PMID:
24375686
DOI:
10.1002/prot.24503
[Indexed for MEDLINE]
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