Identification of a novel allosteric binding site in the CXCR2 chemokine receptor

P. de Kruijf; H.D. Lim; L. Roumen; V.A. Renjaan; J. Zhao; M.J. Webb; D.A. Auld; J.C.H.M Wijkmans; G.J.R. Zaman; M.J. Smit; C. de Graaf; R. Leurs

doi:10.1124/mol.111.073825

Identification of a novel allosteric binding site in the CXCR2 chemokine receptor

P. de Kruijf, H.D. Lim, L. Roumen, V.A. Renjaan, J. Zhao, M.J. Webb, D.A. Auld, J.C.H.M Wijkmans, G.J.R. Zaman, M.J. Smit, C. de Graaf, R. Leurs

Research output: Contribution to Journal › Article › Academic › peer-review

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 (Phe130

Original language	English
Pages (from-to)	1108-1118
Number of pages	10
Journal	Molecular Pharmacology
Volume	80
DOIs	https://doi.org/10.1124/mol.111.073825
Publication status	Published - 2011

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title = "Identification of a novel allosteric binding site in the CXCR2 chemokine receptor",

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 (Phe130",

author = "{de Kruijf}, P. and H.D. Lim and L. Roumen and V.A. Renjaan and J. Zhao and M.J. Webb and D.A. Auld and J.C.H.M Wijkmans and G.J.R. Zaman and M.J. Smit and {de Graaf}, C. and R. Leurs",

year = "2011",

doi = "10.1124/mol.111.073825",

language = "English",

volume = "80",

pages = "1108--1118",

journal = "Molecular Pharmacology",

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TY - JOUR

T1 - Identification of a novel allosteric binding site in the CXCR2 chemokine receptor

AU - de Kruijf, P.

AU - Lim, H.D.

AU - Roumen, L.

AU - Renjaan, V.A.

AU - Zhao, J.

AU - Webb, M.J.

AU - Auld, D.A.

AU - Wijkmans, J.C.H.M

AU - Zaman, G.J.R.

AU - Smit, M.J.

AU - de Graaf, C.

AU - Leurs, R.

PY - 2011

Y1 - 2011

N2 - 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 (Phe130

AB - 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 (Phe130

U2 - 10.1124/mol.111.073825

DO - 10.1124/mol.111.073825

M3 - Article

SN - 0026-895X

VL - 80

SP - 1108

EP - 1118

JO - Molecular Pharmacology

JF - Molecular Pharmacology

ER -

Identification of a novel allosteric binding site in the CXCR2 chemokine receptor

Abstract

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