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Molecular characterization of oxysterol binding to the Epstein-Barr virus-induced receptor 2 (GPR183)

Benned-Jensen, Tau and Norm, Christoffer and Laurent, Stephane and Medom Madsen, Christian and Niss Arfelt, Kristine and Wolf, Romain and Frimurer, Thomas and Sailer, Andreas and Rosenkilde, Mette (2012) Molecular characterization of oxysterol binding to the Epstein-Barr virus-induced receptor 2 (GPR183). Journal of Biological Chemistry, 287 (42). pp. 35470-35483. ISSN 0021-9258


Oxysterols are oxygenated cholesterol derivates that are emerging as a physiologically important group of molecules. Although they regulate a range of cellular processes, only few oxysterol-binding effector proteins have been identified and the knowledge of their binding mode is limited. Recently, the family of G protein-coupled seven transmembrane-spanning receptors (7TM receptors) was added to this group. Specifically, the Epstein-Barr virus-induced gene 2 (EBI2) was shown to be activated by several oxysterols, most potently by 7α,25-dihydroxycholesterol (7α,25-OHC). Based on mutational analysis it is here suggested that 7α,25-OHC binds to EBI2 via hydrogen bonding between its three OH-groups and the receptor residues R87 in TM-II (position II:20/2.60), Y116 in TM-III (III:13/3.37) and Y260 in TM-VI (VI:16/6.51). Mutating these residues to Ala and/or Phe, results in a severe decrease in agonist binding and receptor activation. In addition, Y112 (position III:09/3.33) is also involved in 7α,25-OHC binding but via hydrophobic interactions. EBI2 homology modeling suggests that R87 interacts with the 25-OH group, Y116 with the 3-OH and Y260 with the 7α-OH. Finally, we show that position II:20/2.60 in general constitutes an important anchor point for ligand binding in receptors carrying a positively charged residue at this position. This group is dominated by lipid- and nucleotide-activated receptors, here exemplified by CysLT1 and 2 and the nucleotide-activated receptors P2Y12 and P2Y14. In conclusion, we present the first molecular characterization of oxysterol binding to a 7TM receptor and identify a positive charge in the top of TM-II as a general ligand anchor point for certain 7TM receptors.

Item Type: Article
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Keywords: EBI2, GPCR, oxysterol, mutagenesis
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14


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