Stereospecificity of reactions catalyzed by HIV-1 integrase

The retroviral integrase catalyzes two successive chemical reactions essent ial for integration of the retroviral genome into a host chromosome: 3' end processing, in which a dinucleotide is cleaved from each 3' end of the vir al DNA; and the integration reaction itself, in which the resulting recesse d 3' ends of the viral DNA are joined to the host DNA. We have examined the stereospecificity of human immunodeficiency virus type 1 integrase for pho sphorothioate substrates in these reactions and in a third reaction, disint egration, which is macroscopically the reverse of integration. Integrase pr eferentially catalyzed end processing and integration of a substrate with t he (R-p)-phosphorothioate stereoisomer at the reaction center and disintegr ation of a substrate with an (S-p)-phosphorothiate at the reaction center. These results suggest a model for the architecture of the active site of in tegrase, and its interactions with key features of the viral and target DNA .