ArticleProceedings of the National Academy of Sciences of the United States of America2014
GTP activator and dNTP substrates of HIV-1 restriction factor SAMHD1 generate a long-lived activated state.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 69 papers.
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Who cites it
69 citing papers in PubMed, 102 citations in OpenAlex.
- Transition Metal Activation Reframes SAMHD1 Regulation.ACS chemical biology · 2026Article
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- Transition metal activation reframes SAMHD1 regulation.bioRxiv : the preprint server for biology · 2026Article
- Allosteric targeting with antiviral nucleotide analogs allows fine-tuning of SAMHD1 dNTPase activity.The Journal of biological chemistry · 2026Article
- Continuous assay for the dNTP triphosphohydrolase of activated SAMHD1.Analytical biochemistry · 2026Article
- ssDNA and ssRNA Promote Phase Condensation of SAMHD1.Biochemistry · 2025Article
- Inhibitors of SAMHD1 Obtained from Chemical Tethering to the Guanine Antiviral Acyclovir.Biochemistry · 2025Article
- SAMHD1 shapes deoxynucleotide triphosphate homeostasis by interconnecting the depletion and biosynthesis of different dNTPs.Nature communications · 2025Article
- Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis.Nature communications · 2024Article
- Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1 via a comprehensive screening funnel.iScience · 2024Article
- Guanine-containing ssDNA and RNA induce dimeric and tetrameric structural forms of SAMHD1.Nucleic acids research · 2023Article
- Deoxyguanosine-Linked Bifunctional Inhibitor of SAMHD1 dNTPase Activity and Nucleic Acid Binding.ACS chemical biology · 2023Article
- Discovery of a novel nucleoside immune signaling molecule 2'-deoxyguanosine in microbes and plants.Journal of advanced research · 2023Article
- SAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks.Nature communications · 2022Article
- Targeting the DNA damage response and repair in cancer through nucleotide metabolism.Molecular oncology · 2022Review
- Review
- Phosphorylation of SAMHD1 Thr592 increases C-terminal domain dynamics, tetramer dissociation and ssDNA binding kinetics.Nucleic acids research · 2022Article
- Structural insights into Cullin4-RING ubiquitin ligase remodelling by Vpr from simian immunodeficiency viruses.PLoS pathogens · 2021Article
- Probing the Catalytic Mechanism and Inhibition of SAMHD1 Using the Differential Properties of RBiochemistry · 2021Article
- The Chemokine CCL5 Inhibits the Replication of Influenza A Virus Through SAMHD1 Modulation.Frontiers in cellular and infection microbiology · 2021Article
9 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The HIV-1 restriction factor sterile α-motif/histidine-aspartate domain-containing protein 1 (SAMHD1) is a tetrameric protein that catalyzes the hydrolysis of all dNTPs to the deoxynucleoside and tripolyphosphate, which effectively depletes the dNTP substrates of HIV reverse transcriptase. Here, we establish that SAMHD1 is activated by GTP binding to guanine-specific activator sites (A1) as well as coactivation by substrate dNTP binding to a distinct set of nonspecific activator sites (A2). Combined activation by GTP and dNTPs results in a long-lived tetrameric form of SAMHD1 that persists for hours, even after activating nucleotides are withdrawn from the solution. These results reveal an ordered model for assembly of SAMHD1 tetramer from its inactive monomer and dimer forms, where GTP binding to the A1 sites generates dimer and dNTP binding to the A2 and catalytic sites generates active tetramer. Thus, cellular regulation of active SAMHD1 is not determined by GTP alone but instead, the levels of all dNTPs and the generation of a persistent tetramer that is not in equilibrium with free activators. The significance of the long-lived activated state is that SAMHD1 can remain active long after dNTP pools have been reduced to a level that would lead to inactivation. This property would be important in resting CD4(+) T cells, where dNTP pools are reduced to nanomolar levels to restrict infection by HIV-1.
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Registered trials
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