eTopic 9.1 The Transposase for a Bacterial Transposon Resembles the Integrase for HIV-1

FDA-approved therapies for acquired immune deficiency syndrome (AIDS) caused by the HIV viruses have several problems in terms of tolerability and development of viral resistance, thus emphasizing the importance of new targets for treating HIV infections. One such target is the HIV integrase protein. Integrase activity is essential for retroviral infection because it mediates a mandatory step in the HIV replication process: the integration of the viral complementary DNA (cDNA) into the human genome (the HIV genome in the virus is made of RNA but is reversed-transcribed into cDNA before integration). The similarity in structure between HIV integrase and the transposase enzyme of the bacterial Tn5 transposon (Fig. 1) suggested the Tn5 transposase could be used as a surrogate target to screen large numbers of compounds (called a high-throughput screen) for integrase inhibiton activity. This idea was affirmed by a study showing that in vitro screening of a library of compounds against Tn5 transposase identified several compounds that also proved to be inhibitors of HIV-1 integrase.


Figure 1  Comparison of the catalytic regions for HIV-1 integrase and Tn5 transposase.  Note the similarity in structures. The alpha helices are shown in red, the beta sheets are blue, and the catalytic residues are green. Both enzymes contain a five-strand mixed beta sheet and the DDE motif (aspartate/aspartate/glutamate) of catalytic residues. (PDB codes: 1BIH, 1MUH)