title: The structure of an HIV-1 specific cell entry inhibitor in complex with the HIV-1 gp41 trimeric core.
abstract: The three-dimensional structure of the complex between an HIV-1 cell-entry inhibitor selected from screening a combinatorial library of non-natural building blocks and the central, trimeric, coiled-coil core of HIV-1 gp41 has been determined by X-ray crystallography. The biased combinatorial library was designed to identify ligands binding in nonpolar pockets on the surface of the coiled-coil core of gp41. The crystal structure shows that the non-peptide moiety of the inhibitor binds to the targeted cavity in two different binding modes. This result suggests a strategy for increasing inhibitor potency by use of a second-generation combinatorial library designed to give simultaneous occupancy of both binding sites.
authors.affiliation: Laboratory of Molecular Medicine, The Children's Hospital, Boston, MA 02115, USA.
authors.forename: G
authors.initials: G
authors.lastname: Zhou
authors.forename: M
authors.initials: M
authors.lastname: Ferrer
authors.forename: R
authors.initials: R
authors.lastname: Chopra
authors.forename: T M
authors.initials: TM
authors.lastname: Kapoor
authors.forename: T
authors.initials: T
authors.lastname: Strassmaier
authors.forename: W
authors.initials: W
authors.lastname: Weissenhorn
authors.forename: J J
authors.initials: JJ
authors.lastname: Skehel
authors.forename: D
authors.initials: D
authors.lastname: Oprian
authors.forename: S L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: S C
authors.initials: SC
authors.lastname: Harrison
authors.forename: D C
authors.initials: DC
authors.lastname: Wiley
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D018360:Crystallography, X-Ray; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000187:drug effects* / Q000378:metabolism; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D018716:Molecular Mimicry; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D008024:Ligands; D010455:Peptides