Single amino acid substitution in HIV-1 integrase catalytic core causes a dramatic shift in inhibitor selectivity |
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Authors: | Al-Mawsawi Laith Q Sechi Mario Neamati Nouri |
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Institution: | Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA 90089, USA. |
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Abstract: | HIV-1 integrase (IN) mediates the insertion of viral cDNA into the cell genome, a vital process for replication. This step is catalyzed by two separate DNA reaction events, termed 3'-processing and strand transfer. Here, we show that six inhibitors from five structurally different classes of compounds display a selectivity shift towards preferential strand transfer inhibition over the 3'-processing activity of IN when a single serine is substituted at position C130. Even though IN utilizes the same active site for both reactions, this finding suggests a distinct conformational dissimilarity in the mechanistic details of each IN catalytic event. |
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Keywords: | HIV-1 human immunodeficiency virus type 1 IN integrase WT wild type SM soluble double mutant (F185K/C280S) integrase protein |
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