Structure of the catalytic domain of avian sarcoma virus integrase with a bound HIV-1 integrase-targeted inhibitor.
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.
Lubkowski
J
J
Macromolecular Structure Laboratory, Advanced BioScience Laboratories-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
Yang
F
F
Alexandratos
J
J
Wlodawer
A
A
Zhao
H
H
Burke
T R
TR
Neamati
N
N
Pommier
Y
Y
Merkel
G
G
Skalka
A M
AM
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
D019428:HIV Integrase Inhibitors; D009282:Naphthalenesulfonates; C112235:4-(acetylamino)-5-hydroxy-2,7-naphthalenedisulfonic acid; D008345:Manganese; D019426:Integrases