title: Analysis of binding sites for the new small-molecule CCR5 antagonist TAK-220 on human CCR5.
abstract: G protein-coupled receptor CCR5 is the main coreceptor for macrophage-tropic human immunodeficiency virus type 1 (HIV-1), and various small-molecule CCR5 antagonists are being developed to treat HIV-1 infection. It has been reported that such CCR5 antagonists, including TAK-779, bind to a putative binding pocket formed by transmembrane domains (TMs) 1, 2, 3 and 7 of CCR5, indicating the importance of the conformational changes of the TMs during virus entry. In this report, using a single-round infection assay with human CCR5 and its substitution mutants, we demonstrated that a new CCR5 antagonist, TAK-220, shares the putative interacting amino acid residues Asn252 and Leu255 in TM6 with TAK-779 but also requires the distinct residues Gly163 and Ile198 in TMs 4 and 5, respectively, for its inhibitory effect. We suggested that, together with molecular models of the interactions between the drugs and CCR5, the inhibitory activity of TAK-220 could involve direct interactions with amino acid residues in TMs 4, 5, and 6 in addition to those in the previously postulated binding pocket. The possible interaction of drugs with additional regions of the CCR5 molecule would help to develop a new small-molecule CCR5 antagonist.
authors.affiliation: Department of Microbiology, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi, Osaka 570-8506, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Nishikawa
authors.forename: Katsunori
authors.initials: K
authors.lastname: Takashima
authors.forename: Toshiya
authors.initials: T
authors.lastname: Nishi
authors.forename: Rika A
authors.initials: RA
authors.lastname: Furuta
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Fujisawa
mesh_terms: D000577:Amides / Q000494:pharmacology; D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D065100:CCR5 Receptor Antagonists; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010880:Piperidines / Q000378:metabolism* / Q000493:pharmacokinetics; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D019713:Receptors, CCR5 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D010880:Piperidines; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; C506969:TAK-220; C119369:TAK 779