ArticleNucleic acids research2006
Role of metal ions in catalysis by HIV integrase analyzed using a quantitative PCR disintegration assay.
Article in Nucleic acids research, 2006. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 27 citations in OpenAlex.
- Sensitive Pathogen Detection and Drug Resistance Characterization Using Pathogen-Derived Enzyme Activity Amplified by LAMP or CRISPR-Cas.medRxiv : the preprint server for health sciences · 2024Article
- Structure of a HIV-1 IN-Allosteric inhibitor complex at 2.93 Å resolution: Routes to inhibitor optimization.PLoS pathogens · 2023Article
- Allosteric HIV Integrase Inhibitors Promote Formation of Inactive Branched Polymers via Homomeric Carboxy-Terminal Domain Interactions.Structure (London, England : 1993) · 2021Article
- Influence of the amino-terminal sequence on the structure and function of HIV integrase.Retrovirology · 2020Article
- Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase.PLoS biology · 2016Article
- Alternative nucleophilic substrates for the endonuclease activities of human immunodeficiency virus type 1 integrase.Virology · 2012Article
- Metal cofactors in the structure and activity of the fowlpox resolvase.Journal of molecular biology · 2010Article
- The Interaction Between Lentiviral Integrase and LEDGF: Structural and Functional Insights.Viruses · 2009Article
- MetalDetector: a web server for predicting metal-binding sites and disulfide bridges in proteins from sequence.Bioinformatics (Oxford, England) · 2008Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Paired metal ions have been proposed to be central to the catalytic mechanisms of RNase H nucleases, bacterial transposases, Holliday junction resolvases, retroviral integrases and many other enzymes. Here we present a sensitive assay for DNA transesterification in which catalysis by human immunodeficiency virus-type 1 (HIV-1) integrase (IN) connects two DNA strands (disintegration reaction), allowing detection using quantitative PCR (qPCR). We present evidence suggesting that the three acidic residues of the IN active site function through metal binding using metal rescue. In this method, the catalytic acidic residues were each substituted with cysteines. Mn2+ binds tightly to the sulfur atoms of the cysteine residues, but Mg2+ does not. We found that Mn2+, but not Mg2+, could rescue catalysis of each cysteine-substituted enzyme, providing evidence for functionally important metal binding by all three residues. We also used the PCR-boosted assay to show that HIV-1 IN could carry out transesterification reactions involving DNA 5' hydroxyl groups as well as 3' hydroxyls as nucleophiles. Lastly, we show that Mn2+ by itself (i.e. without enzyme) can catalyze formation of a low level of PCR-amplifiable product under extreme conditions, allowing us to estimate the rate enhancement due to the IN-protein scaffold as at least 60 million-fold.
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