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 dom ain of avian sarcoma virus integrase (ASV IN) were solved at 1.9- to 2 .0-Angstrom resolution at two pH values, with and without Mn2+ cations . This inhibitor (Y-3), originally identified in a screen for inhibito rs of the catalytic activity of HIV type 1 integrase (HIV-1 IN), was f ound 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 acti ve site, interacts with the flexible loop, alters loop conformation, a nd affects the conformations of active site residues. As crystallized, a Y-3 molecule stacks against its symmetry-related mate. Preincubatio n of IN with metal cations does not prevent inhibition, and Y-3 bindin g does not prevent binding of divalent cations to IN. Three compounds chemically related to Y-3 also were investigated, but no binding was o bserved in the crystals. Our results identify the structural elements of the inhibitor that likely determine its binding properties.