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 JournalArticleAcademicpeer-review


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 languageEnglish
Pages (from-to)1108-1118
Number of pages10
JournalMolecular Pharmacology
Publication statusPublished - 2011


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