Elucidation of binding sites of dual antagonists in the human chemokine receptors CCR2 and CCR5

Spencer E. Hall, Allen Mao, Vicky Nicolaidou, Mattea Finelli, Emma L. Wise, Belinda Nedjai, Julie Kanjanapangka, Paymann Harirchian, Deborah Chen, Victor Selchau, Sofia Ribeiro, Sabine Schyler, James E. Pease, Richard Horuk, Nagarajan Vaidehi

Research output: Contribution to journalArticlepeer-review

Abstract

Design of dual antagonists for the chemokine receptors CCR2 and CCR5 will be greatly facilitated by knowledge of the structural differences of their binding sites. Thus, we computationally predicted the binding site of the dual CCR2/CCR5 antagonist N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H- benzohepten-8-yl] carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium (TAK-779), and a CCR2-specific antagonist N-(carbamoylmethyl)-3-trifluoromethyl benzamido-parachlorobenzyl 3-aminopyrrolidine (Teijin compound 1) in an ensemble of predicted structures of human CCR2 and CCR5. Based on our predictions of the protein-ligand interactions, we examined the activity of the antagonists for cells expressing thirteen mutants of CCR2 and five mutants of CCR5. The results show that residues Trp982.60 and Thr2927.40 contribute significantly to the efficacy of both TAK-779 and Teijin compound 1, whereas His1213.33 and Ile2636.55 contribute significantly only to the antagonistic effect of Teijin compound 1 at CCR2. Mutation of residues Trp862.60 and Tyr1083.32 adversely affected the efficacy of TAK-779 in antagonizing CCR5-mediated chemotaxis. Y49A1.39 and E291A7.39 mutants of CCR2 showed a complete loss of CCL2 binding and chemotaxis, despite robust cell surface expression, suggesting that these residues are critical in maintaining the correct receptor architecture. Modeling studies support the hypothesis that the residues Tyr491.39, Trp982.60, Tyr1203.32, and Glu2917.39 of CCR2 form a tight network of aromatic cluster and polar contacts between transmembrane helices 1, 2, 3, and 7.

Original languageEnglish
Pages (from-to)1325-1336
Number of pages12
JournalMolecular Pharmacology
Volume75
Issue number6
DOIs
Publication statusPublished - Jun 2009

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