Structure of the Catalytic Domain of Avian Sarcoma Virus Integrase with a Bound HIV-1 Integrase-Targeted Inhibitor

• Published in: Proceedings of the National Academy of Sciences - PNAS 1998-04, Vol.95 (9), p.4831-4836
• Main Authors: Lubkowski, Jacek, Yang, Fan, Alexandratos, Jerry, Wlodawer, Alexander, Zhao, He, Burke, Terrence R., Neamati, Nouri, Pommier, Yves, Merkel, George, Skalka, Anna Marie
• Format: Article
• Language: English
• Subjects: Active sites; AIDS/HIV; Atomic interactions; Atoms; Avian Sarcoma Viruses - enzymology; Binding Sites; Biological Sciences; Biology; Catalysts; Crystallography, X-Ray; Crystals; Enzymes; HIV; HIV 1; HIV Integrase Inhibitors - chemistry; Human immunodeficiency virus; Hydrogen-Ion Concentration; Integrases - ultrastructure; Manganese; Models, Molecular; Molecular interactions; Molecular Sequence Data; Molecules; Naphthalenesulfonates - chemistry; Protein Structure, Tertiary
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.95.9.4831

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- angstrom 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.