title: A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5.
abstract: HIV-1 entry into CD4(+) cells requires the sequential interactions of the viral envelope glycoproteins with CD4 and a coreceptor such as the chemokine receptors CCR5 and CXCR4. A plausible approach to blocking this process is to use small molecule antagonists of coreceptor function. One such inhibitor has been described for CCR5: the TAK-779 molecule. To facilitate the further development of entry inhibitors as antiviral drugs, we have explored how TAK-779 acts to prevent HIV-1 infection, and we have mapped its site of interaction with CCR5. We find that TAK-779 inhibits HIV-1 replication at the membrane fusion stage by blocking the interaction of the viral surface glycoprotein gp120 with CCR5. We could identify no amino acid substitutions within the extracellular domain of CCR5 that affected the antiviral action of TAK-779. However, alanine scanning mutagenesis of the transmembrane domains revealed that the binding site for TAK-779 on CCR5 is located near the extracellular surface of the receptor, within a cavity formed between transmembrane helices 1, 2, 3, and 7.
authors.affiliation: Aaron Diamond AIDS Research Center, The Rockefeller University, New York, NY 10016, USA. tdragic@aecom.yu.edu
authors.forename: T
authors.initials: T
authors.lastname: Dragic
authors.forename: A
authors.initials: A
authors.lastname: Trkola
authors.forename: D A
authors.initials: DA
authors.lastname: Thompson
authors.forename: E G
authors.initials: EG
authors.lastname: Cormier
authors.forename: F A
authors.initials: FA
authors.lastname: Kajumo
authors.forename: E
authors.initials: E
authors.lastname: Maxwell
authors.forename: S W
authors.initials: SW
authors.lastname: Lin
authors.forename: W
authors.initials: W
authors.lastname: Ying
authors.forename: S O
authors.initials: SO
authors.lastname: Smith
authors.forename: T P
authors.initials: TP
authors.lastname: Sakmar
authors.forename: J P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D000577:Amides / Q000493:pharmacokinetics / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D065100:CCR5 Receptor Antagonists; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D016466:CHO Cells; D002462:Cell Membrane / Q000821:virology; D006224:Cricetinae; D015686:Gene Products, env / Q000502:physiology; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000276:immunology / Q000821:virology*; D008561:Membrane Fusion / Q000187:drug effects; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017433:Protein Structure, Secondary; D000644:Quaternary Ammonium Compounds / Q000493:pharmacokinetics / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000737:chemistry* / Q000502:physiology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D015686:Gene Products, env; D015699:HIV Envelope Protein gp120; D000644:Quaternary Ammonium Compounds; D019713:Receptors, CCR5; D011994:Recombinant Proteins; C119369:TAK 779