ArticlePloS one2017
Substrates and Inhibitors of SAMHD1.
Article in PloS one, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
38 citing papers in PubMed, 64 citations in OpenAlex.
- Nucleotide Metabolism in Health and Disease.MedComm · 2026Review
- Allosteric targeting with antiviral nucleotide analogs allows fine-tuning of SAMHD1 dNTPase activity.The Journal of biological chemistry · 2026Article
- IMPDH inhibition enhances cytarabine efficacy in SAMHD1-expressing leukaemia cells via guanine nucleotide depletion.Molecular oncology · 2026Article
- Continuous assay for the dNTP triphosphohydrolase of activated SAMHD1.Analytical biochemistry · 2026Article
- 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
- SAMHD1 expression is a surrogate marker of immune infiltration and determines prognosis after neoadjuvant chemotherapy in early breast cancer.Cellular oncology (Dordrecht, Netherlands) · 2024Article
- SAMHD1 single nucleotide polymorphisms impact outcome in children with newly diagnosed acute myeloid leukemia.Blood advances · 2023Article
- Targeting the DNA damage response and repair in cancer through nucleotide metabolism.Molecular oncology · 2022Review
- Review
- SAMHD1 in cancer: curse or cure?Journal of molecular medicine (Berlin, Germany) · 2022Review
- Review
- Differences between intrinsic and acquired nucleoside analogue resistance in acute myeloid leukaemia cells.Journal of experimental & clinical cancer research : CR · 2021Article
- Structural and functional characterization explains loss of dNTPase activity of the cancer-specific R366C/H mutant SAMHD1 proteins.The Journal of biological chemistry · 2021Article
- Probing the Catalytic Mechanism and Inhibition of SAMHD1 Using the Differential Properties of RBiochemistry · 2021Article
- Dual roles of SAMHD1 in tumor development and chemoresistance to anticancer drugs.Oncology letters · 2021Review
- The HD-Domain Metalloprotein Superfamily: An Apparent Common Protein Scaffold with Diverse Chemistries.Catalysts (Basel, Switzerland) · 2020Article
- Downregulation of GLI3 Expression Mediates Chemotherapy Resistance in Acute Myeloid Leukemia.International journal of molecular sciences · 2020Article
- SAMHD1 is a key regulator of the lineage-specific response of acute lymphoblastic leukaemias to nelarabine.Communications biology · 2020Article
- Crystal structures of SAMHD1 inhibitor complexes reveal the mechanism of water-mediated dNTP hydrolysis.Nature communications · 2020Article
Corrections and comments
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Authors and funding
11 authors at 3 institutions in 2 countries.
Funding
Abstract
SAMHD1 hydrolyzes 2'-deoxynucleoside-5'-triphosphates (dNTPs) into 2'-deoxynucleosides and inorganic triphosphate products. In this paper, we evaluated the impact of 2' sugar moiety substitution for different nucleotides on being substrates for SAMHD1 and mechanisms of actions for the results. We found that dNTPs ((2'R)-2'-H) are only permissive in the catalytic site of SAMHD1 due to L150 exclusion of (2'R)-2'-F and (2'R)-2'-OH nucleotides. However, arabinose ((2'S)-2'-OH) nucleoside-5'-triphosphates analogs are permissive to bind in the catalytic site and be hydrolyzed by SAMHD1. Moreover, when the (2'S)-2' sugar moiety is increased to a (2'S)-2'-methyl as with the SMDU-TP analog, we detect inhibition of SAMHD1's dNTPase activity. Our computational modeling suggests that (2'S)-2'-methyl sugar moiety clashing with the Y374 of SAMHD1. We speculate that SMDU-TP mechanism of action requires that the analog first docks in the catalytic pocket of SAMHD1 but prevents the A351-V378 helix conformational change from being completed, which is needed before hydrolysis can occur. Collectively we have identified stereoselective 2' substitutions that reveal nucleotide substrate specificity for SAMHD1, and a novel inhibitory mechanism for the dNTPase activity of SAMHD1. Importantly, our data is beneficial for understanding if FDA-approved antiviral and anticancer nucleosides are hydrolyzed by SAMHD1 in vivo.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.