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Determination of the site of ligand binding on the Sigma1 Receptor
Author(s) -
Schrock Joel M,
Islam Mohammad M,
Kim Felix J,
Grinnell Steven G,
Pasternak Gavril W
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1174.5
Subject(s) - binding site , chemistry , receptor , biophysics , antagonist , mechanism of action , stereochemistry , cooperative binding , ligand (biochemistry) , biochemistry , biology , in vitro
The Sigma1 Receptor (Sig1R) is a 26 kilodalton integral membrane protein which shares no structural homology with any traditional receptor family. Despite the description of Sig1R effects in many different signaling pathways, the mechanism of Sig1R action has not been determined. Historically, the distinction between Sig1R agonists and antagonists has been made based on the pharmacological response in specific systems, which has added to the difficulty in determining the mechanism of Sig1R action. Our laboratory has focused on determining the site of ligand binding on the Sig1R in order to better define Sig1R agonists and antagonists. Using circular dichroism, Sig1R antagonists but not agonists stabilize the C‐terminal tail of the Sig1R, indicating binding. In order to further define the binding sites of Sig1R agonists and antagonists, [ 125 I]1‐(4‐Iodophenyl)‐3‐(2‐adamantyl)guanidine (IPAG, a Sig1R antagonist) was synthesized. IPAG bound with high affinity to both the full‐length Sig1R as well as the C‐terminal tail of the Sig1R, indicating that the binding site of IPAG is in the C‐terminal tail. Antagonists potently lowered binding of [ 125 I]IPAG to the C‐terminal tail, while Sig1R agonists did not compete [ 125 I]IPAG binding with high affinity, potentially indicating different binding sites for Sig1R agonists and antagonists.