MRC National Institute for Medical Research, London
Science for Health
Crystal structure reveals unusual enzyme activity of HIV-1 restriction factor
07 November 2011
Scientists at NIMR and the University of Manchester have moved closer to understanding how the SAMHD1 protein helps to block the human immunodeficiency virus HIV-1. The research is published online in Nature.
In human cells there are several proteins, termed restriction factors, which inhibit HIV-1 infection but in most cases the mechanism by which these factors inhibit retroviral infection is poorly understood. The most recently discovered restriction factor is SAMHD1, a protein expressed in dendritic and other myeloid immune cells and able to block HIV-1 replication in these cell types. However the cellular functions and the mechanism of SAMHD1 mediated inhibition of HIV-1 has remained a mystery.
Ian Taylor's group, in NIMR's Division of Molecular Structure, has worked on this question with teams from the University of Manchester, from NIMR's Division of Virology and Division of Mycobacterial Research along with the MRC Biomedical NMR Centre. They determined the crystal structure of the catalytic core of the SAMHD1 molecule and also determined exactly what SAMHD1's enzyme activity is.
By systematically examining potential substrate molecules such as nucleic acids and nucleotides they were able to elucidate SAMHD1's unusual enzymatic activity. The enzyme hydrolyses deoxyribonucleoside triphosphates – the precursors of DNA synthesis - to the constituent nucleoside and inorganic triphosphate. In this way SAMHD1 is able to deprive HIV-1 of the building blocks needed to replicate its genome and block reverse transcription.
Unlike other restriction factors that target viral components the action of SAMHD1 is to make the intracellular environment itself inhibitory to HIV-1 replication. This activity may not be exclusive to HIV-1; other viruses may also be inhibited in dendritic cells by SAMHD1. The clinical implications are that if we can manipulate SAMHD1 activity with drug molecules we may also be able to either repress HIV-1 replication further or expose the virus to the immune system by inhibiting SAMHD1 activity. We now wish to define more precisely, at a molecular level, how SAMHD1 functions. This will pave the way for new therapeutic approaches to HIV-1 and even vaccine development.
Ian Taylor
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Crystal structure of the extended HD domain of human SAMHD1
Original article
HIV-1 restriction factor SAMHD1 is a deoxynucleoside triphosphate triphosphohydrolase
David C. Goldstone, Valerie Ennis-Adeniran, Joseph J. Hedden, Harriet C. T. Groom, Gillian I. Rice, Evangelos Christodoulou, Philip A. Walker, Geoff Kelly, Lesley F. Haire, Melvyn W. Yap, Luiz Pedro S. de Carvalho, Jonathan P. Stoye, Yanick J. Crow, Ian A. Taylor & Michelle Webb (2011)
Nature, Epub ahead of print. Publisher abstract.
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