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Research ArticleArticle

Identification of Structural Motifs Critical for Epstein-Barr Virus-Induced Molecule 2 Function and Homology Modeling of the Ligand Docking Site

Li Zhang, Amy Y. Shih, Xia V. Yang, Chester Kuei, Jiejun Wu, Xiaohu Deng, Neelakandha S. Mani, Taraneh Mirzadegan, Siquan Sun, Timothy W. Lovenberg and Changlu Liu
Molecular Pharmacology December 2012, 82 (6) 1094-1103; DOI: https://doi.org/10.1124/mol.112.080275
Li Zhang
Janssen Pharmaceutical Research and Development, San Diego, California
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Amy Y. Shih
Janssen Pharmaceutical Research and Development, San Diego, California
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Xia V. Yang
Janssen Pharmaceutical Research and Development, San Diego, California
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Chester Kuei
Janssen Pharmaceutical Research and Development, San Diego, California
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Jiejun Wu
Janssen Pharmaceutical Research and Development, San Diego, California
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Xiaohu Deng
Janssen Pharmaceutical Research and Development, San Diego, California
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Neelakandha S. Mani
Janssen Pharmaceutical Research and Development, San Diego, California
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Taraneh Mirzadegan
Janssen Pharmaceutical Research and Development, San Diego, California
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Siquan Sun
Janssen Pharmaceutical Research and Development, San Diego, California
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Timothy W. Lovenberg
Janssen Pharmaceutical Research and Development, San Diego, California
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Changlu Liu
Janssen Pharmaceutical Research and Development, San Diego, California
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Abstract

Epstein-Barr virus-induced molecule 2 (EBI2) (also known as G-protein–coupled receptor 183) is a G-protein–coupled receptor (GPCR) that is best known for its role in B cell migration and localization. Our recent deorphanization effort led to the discovery of 7α,25-dihydroxycholesterol (7α,25-OHC) as the endogenous ligand for EBI2, which provides a tool for mechanistic studies of EBI2 function. Because EBI2 is the first GPCR known to bind and to be activated by an oxysterol, the goal of this study was to understand the molecular and structural bases for its ligand-dependent activation; this was achieved by identifying structural moieties in EBI2 or in 7α,25-OHC that might affect receptor-ligand interactions. By using a series of chemically related OHC analogs, we demonstrated that all three hydroxyl groups in 7α,25-OHC contributed to ligand-induced activation of the receptor. To determine the location and composition of the ligand binding domain in EBI2, we used a site-directed mutagenesis approach and generated mutant receptors with single amino acid substitutions at selected positions of interest. Biochemical and pharmacological profiling of these mutant receptors allowed for structure-function analyses and revealed critical motifs that likely interact with 7α,25-OHC. By using a hybrid β2-adrenergic receptor–C-X-C chemokine receptor type 4 structure as a template, we created a homology model for EBI2 and optimized the docking of 7α,25-OHC into the putative ligand binding site, so that the hydroxyl groups interact with residues Arg87, Asn114, and Glu183. This model of ligand docking yields important structural insight into the molecular mechanisms mediating EBI2 function and may facilitate future efforts to design novel therapeutic agents that target EBI2.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    http://dx.doi.org/10.1124/mol.112.080275.

  • ABBREVIATIONS:

    EBI2
    Epstein-Barr virus-induced molecule 2
    CXCR
    C-X-C chemokine receptor
    β2AR
    β2-adrenergic receptor
    ECL
    extracellular loop
    GPCR
    G-protein–coupled receptor
    GTPγS
    guanosine 5′-O-(3-thio)triphosphate
    OHC
    hydroxycholesterol
    PDB
    Protein Data Bank
    TM
    transmembrane region
    GPR
    G-protein–coupled receptor.

  • Received June 1, 2012.
  • Accepted August 28, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (6)
Molecular Pharmacology
Vol. 82, Issue 6
1 Dec 2012
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Research ArticleArticle

Insight into Structural Basis of EBI2 Function

Li Zhang, Amy Y. Shih, Xia V. Yang, Chester Kuei, Jiejun Wu, Xiaohu Deng, Neelakandha S. Mani, Taraneh Mirzadegan, Siquan Sun, Timothy W. Lovenberg and Changlu Liu
Molecular Pharmacology December 1, 2012, 82 (6) 1094-1103; DOI: https://doi.org/10.1124/mol.112.080275

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Research ArticleArticle

Insight into Structural Basis of EBI2 Function

Li Zhang, Amy Y. Shih, Xia V. Yang, Chester Kuei, Jiejun Wu, Xiaohu Deng, Neelakandha S. Mani, Taraneh Mirzadegan, Siquan Sun, Timothy W. Lovenberg and Changlu Liu
Molecular Pharmacology December 1, 2012, 82 (6) 1094-1103; DOI: https://doi.org/10.1124/mol.112.080275
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