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- DOI: 10.1038/nature10623
- PMID: 22056990
- UKPMCID: 22056990
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HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase
Goldstone, David C; Ennis-Adeniran, Valerie; Hedden, Joseph J; Groom, Harriet CT; Rice, Gillian I; Christodoulou, Evangelos; Walker, Philip A; Kelly, Geoff; Haire, Lesley F; Yap, Melvyn W; de Carvalho, Luiz Pedro S; Stoye, Jonathan P; Crow, Yanick J; Taylor, Ian A; Webb, Michelle
Nature. 2011;480(7377):379-382.
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Full-text held externally
- DOI: 10.1038/nature10623
- PMID: 22056990
- UKPMCID: 22056990
Abstract
SAMHD1, an analogue of the murine interferon (IFN)-γ-induced gene Mg11 (ref. 1), has recently been identified as a human immunodeficiency virus-1 (HIV-1) restriction factor that blocks early-stage virus replication in dendritic and other myeloid cells and is the target of the lentiviral protein Vpx, which can relieve HIV-1 restriction. SAMHD1 is also associated with Aicardi-Goutières syndrome (AGS), an inflammatory encephalopathy characterized by chronic cerebrospinal fluid lymphocytosis and elevated levels of the antiviral cytokine IFN-α. The pathology associated with AGS resembles congenital viral infection, such as transplacentally acquired HIV. Here we show that human SAMHD1 is a potent dGTP-stimulated triphosphohydrolase that converts deoxynucleoside triphosphates to the constituent deoxynucleoside and inorganic triphosphate. The crystal structure of the catalytic core of SAMHD1 reveals that the protein is dimeric and indicates a molecular basis for dGTP stimulation of catalytic activity against dNTPs. We propose that SAMHD1, which is highly expressed in dendritic cells, restricts HIV-1 replication by hydrolysing the majority of cellular dNTPs, thus inhibiting reverse transcription and viral complementary DNA (cDNA) synthesis.