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J Biol Chem, Vol. 274, Issue 47, 33480-33487, November 19, 1999

Stereospecificity of Reactions Catalyzed by HIV-1 Integrase

Jennifer L. Gerton, Daniel Herschlag^§, and Patrick O. Brown^§¶

From the ^¶ Howard Hughes Medical Institute, ^§ Department of Biochemistry, and  Department of Microbiology and Immunology, Stanford University Medical Center, Stanford, California 94305-5428

The retroviral integrase catalyzes two successive chemical reactions essential 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 viral DNA; and the integration reaction itself, in which the resulting recessed 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 phosphorothioate substrates in these reactions and in a third reaction, disintegration, which is macroscopically the reverse of integration. Integrase preferentially catalyzed end processing and integration of a substrate with the (R_p)-phosphorothioate stereoisomer at the reaction center and disintegration 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 integrase, and its interactions with key features of the viral and target DNA.

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