title: Structural basis for the interaction of CCR5 with a small molecule, functionally selective CCR5 agonist.
abstract: The chemokine receptor CCR5 is an attractive target for HIV-1 drug development, as individuals whose cells lack surface CCR5 expression are highly resistant to HIV-1 infection. CCR5 ligands, such as CCL5/RANTES, effectively inhibit HIV-1 infection by competing for binding opportunities to the CCR5 and inducing its internalization. However, the inherent proinflammatory activity of the chemotactic response of CCR5 ligands has limited their clinical use. In this study, we found that a novel small molecule, functionally selective CCR5 agonist, 2,2-dichloro-1-(triphenylphosphonio)vinyl formamide perchlorate (YM-370749), down-modulates CCR5 from the cell surface without inducing a chemotactic response and inhibits HIV-1 replication. In molecular docking studies of YM-370749 and a three-dimensional model of CCR5 based on the rhodopsin crystal structure as well as binding and functional studies using various CCR5 mutants, the amino acid residues necessary for interaction with YM-370749 were marked. These results provide a structural basis for understanding the activation mechanism of CCR5 and for designing functionally selective agonists as a novel class of anti-HIV-1 agents.
authors.affiliation: Molecular Medicine Research Laboratories, Institute for Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan. yuuji.saita@jp.astellas.com
authors.forename: Yuji
authors.initials: Y
authors.lastname: Saita
authors.forename: Eiichi
authors.initials: E
authors.lastname: Kodama
authors.forename: Masaya
authors.initials: M
authors.lastname: Orita
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kondo
authors.forename: Takahiro
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Kenji
authors.initials: K
authors.lastname: Sudo
authors.forename: Keiko
authors.initials: K
authors.lastname: Kajiwara
authors.forename: Masao
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008253:Macaca mulatta; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000494:pharmacology*; D010472:Perchlorates / Q000737:chemistry* / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D019713:Receptors, CCR5 / Q000819:agonists* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication / Q000187:drug effects
chemical_list: C513867:2,2-dichloro-1-(triphenylphosphonio)vinyl formamide perchlorate; D000998:Antiviral Agents; D009943:Organophosphorus Compounds; D010472:Perchlorates; D019713:Receptors, CCR5; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002118:Calcium