Download MendeleyHIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase
Goldstone, D.C., Ennis-Adeniran, V., Hedden, J.J., Groom, H.C., Rice, G.I., Christodoulou, E., Walker, P.A., Kelly, G., Haire, L.F., Yap, M.W., de Carvalho, L.P., Stoye, J.P., Crow, Y.J., Taylor, I.A., Webb, M.(2011) Nature 480: 379-382
- PubMed: 22056990
- DOI: https://doi.org/10.1038/nature10623
- Primary Citation of Related Structures:
3U1N - PubMed 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.
Organizational Affiliation:
Division of Molecular Structure, MRC National Institute for Medical Research, London NW7 1AA, UK.
