title: Structure of the catalytic domain of avian sarcoma virus integrase with a bound HIV-1 integrase-targeted inhibitor.
abstract: The x-ray structures of an inhibitor complex of the catalytic core domain of avian sarcoma virus integrase (ASV IN) were solved at 1.9- to 2.0-A resolution at two pH values, with and without Mn2+ cations. This inhibitor (Y-3), originally identified in a screen for inhibitors of the catalytic activity of HIV type 1 integrase (HIV-1 IN), was found in the present study to be active against ASV IN as well as HIV-1 IN. The Y-3 molecule is located in close proximity to the enzyme active site, interacts with the flexible loop, alters loop conformation, and affects the conformations of active site residues. As crystallized, a Y-3 molecule stacks against its symmetry-related mate. Preincubation of IN with metal cations does not prevent inhibition, and Y-3 binding does not prevent binding of divalent cations to IN. Three compounds chemically related to Y-3 also were investigated, but no binding was observed in the crystals. Our results identify the structural elements of the inhibitor that likely determine its binding properties.
authors.affiliation: Macromolecular Structure Laboratory, Advanced BioScience Laboratories-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
authors.forename: J
authors.initials: J
authors.lastname: Lubkowski
authors.forename: F
authors.initials: F
authors.lastname: Yang
authors.forename: J
authors.initials: J
authors.lastname: Alexandratos
authors.forename: A
authors.initials: A
authors.lastname: Wlodawer
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.forename: T R
authors.initials: TR
authors.lastname: Burke
authors.forename: N
authors.initials: N
authors.lastname: Neamati
authors.forename: Y
authors.initials: Y
authors.lastname: Pommier
authors.forename: G
authors.initials: G
authors.lastname: Merkel
authors.forename: A M
authors.initials: AM
authors.lastname: Skalka
mesh_terms: D001358:Avian Sarcoma Viruses / Q000201:enzymology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D019428:HIV Integrase Inhibitors / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D019426:Integrases / Q000648:ultrastructure*; D008345:Manganese; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009282:Naphthalenesulfonates / Q000737:chemistry*; D017434:Protein Structure, Tertiary
chemical_list: D019428:HIV Integrase Inhibitors; D009282:Naphthalenesulfonates; C112235:4-(acetylamino)-5-hydroxy-2,7-naphthalenedisulfonic acid; D008345:Manganese; D019426:Integrases