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Research ArticleArticle

Identification of a Novel Allosteric Binding Site in the CXCR2 Chemokine Receptor

Petra de Kruijf, Herman D. Lim, Luc Roumen, Véronique A. Renjaän, Jiuqiao Zhao, Maria L. Webb, Douglas S. Auld, Jac. C.H.M. Wijkmans, Guido J. R. Zaman, Martine J. Smit, Chris de Graaf and Rob Leurs
Molecular Pharmacology December 2011, 80 (6) 1108-1118; DOI: https://doi.org/10.1124/mol.111.073825
Petra de Kruijf
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Herman D. Lim
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Luc Roumen
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Véronique A. Renjaän
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Jiuqiao Zhao
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Maria L. Webb
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Douglas S. Auld
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Jac. C.H.M. Wijkmans
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Guido J. R. Zaman
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Martine J. Smit
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Chris de Graaf
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Rob Leurs
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Abstract

We have shown previously that different chemical classes of small-molecule antagonists of the human chemokine CXCR2 receptor interact with distinct binding sites of the receptor. Although an intracellular binding site for diarylurea CXCR2 antagonists, such as N-(2-bromophenyl)-N′-(7-cyano-1H-benzotriazol-4-yl)urea (SB265610), and thiazolopyrimidine compounds was recently mapped by mutagenesis studies, we now report on an imidazolylpyrimidine antagonist binding pocket in the transmembrane domain of CXCR2. Using different CXCR2 orthologs, chimeric proteins, site-directed mutagenesis, and in silico modeling, we have elucidated the binding mode of this antagonist. Our in silico-guided mutagenesis studies indicate that the ligand binding cavity for imidazolylpyrimidine compounds in CXCR2 is located between transmembrane (TM) helices 3 (Phe1303.36), 5 (Ser2175.44, Phe2205.47), and 6 (Asn2686.52, Leu2716.55) and suggest that these antagonists enter CXCR2 via the TM5-TM6 interface. It is noteworthy that the same interface is postulated as the ligand entry channel in the opsin receptor and is occupied by lipid molecules in the recently solved crystal structure of the CXCR4 chemokine receptor, suggesting a general ligand entrance mechanism for nonpolar ligands to G protein-coupled receptors. The identification of a novel allosteric binding cavity in the TM domain of CXCR2, in addition to the previously identified intracellular binding site, shows the diversity in ligand recognition mechanisms by this receptor and offers new opportunities for the structure-based design of small allosteric modulators of CXCR2 in the future.

Footnotes

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

  • This study was performed within the framework of the Dutch Top Institute Pharma [projects T101-3, D1-105].

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

    doi:10.1124/mol.111.073825.

  • ABBREVIATIONS:

    CXCR
    CXC chemokine receptor
    GPCR
    G-protein coupled receptor
    SB265610
    N-(2-bromophenyl)-N′-(7-cyano-1H-benzotriazol-4-yl)urea
    SCH-527123
    2-hydroxy-N,N-dimethyl-3-{2-[[(R)-1-(5-methyl-furan-2-yl)-propyl]amino]-3,4-dioxo-cyclobut-1-enylamino}-benzamide
    IT1t
    1,3-dicyclohexyl-2-(3-methyl-6,6-dimethyl-5,6-dihydroimidazo[1,2-b] thiazole)-2-thiopseudourea
    ketoprofen
    2-(3-benzoylphenyl)propanoic acid
    CVX15
    Arg-Arg-Nal-Cys-Tyr-Gln-Lys-dPro-Pro-Tyr-Arg-Cit-Cys-Arg-Gly-dPro
    TM
    transmembrane
    PEI
    polyethylenimine
    BSA
    bovine serum albumin fraction V
    GTPγS
    guanosine 5′-O-(3-thio)triphosphate; compound 1, (S)-2-(2-(1H-imidazol-1-yl)-6-(octylthio)pyrimidin-4-ylamino)-N-(3-ethoxypropyl)-4-methylpentanamide
    PCR
    polymerase chain reaction
    H
    human
    B
    baboon
    TBS
    Tris-buffered saline
    WT
    wild type.

  • Received May 27, 2011.
  • Accepted September 23, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 80 (6)
Molecular Pharmacology
Vol. 80, Issue 6
1 Dec 2011
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Research ArticleArticle

Binding Pocket Imidazolylpyrimidine Compound at CXCR2

Petra de Kruijf, Herman D. Lim, Luc Roumen, Véronique A. Renjaän, Jiuqiao Zhao, Maria L. Webb, Douglas S. Auld, Jac. C.H.M. Wijkmans, Guido J. R. Zaman, Martine J. Smit, Chris de Graaf and Rob Leurs
Molecular Pharmacology December 1, 2011, 80 (6) 1108-1118; DOI: https://doi.org/10.1124/mol.111.073825

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Research ArticleArticle

Binding Pocket Imidazolylpyrimidine Compound at CXCR2

Petra de Kruijf, Herman D. Lim, Luc Roumen, Véronique A. Renjaän, Jiuqiao Zhao, Maria L. Webb, Douglas S. Auld, Jac. C.H.M. Wijkmans, Guido J. R. Zaman, Martine J. Smit, Chris de Graaf and Rob Leurs
Molecular Pharmacology December 1, 2011, 80 (6) 1108-1118; DOI: https://doi.org/10.1124/mol.111.073825
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