Crystal structures of SAMHD1 inhibitor complexes reveal the mechanism of water-mediated dNTP hydrolysis

Elizabeth R. Morris, Sarah J. Caswell, Simone Kunzelmann, Laurence H. Arnold, Andrew G. Purkiss, Geoff Kelly and Ian A. Taylor ()
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Elizabeth R. Morris: The Francis Crick Institute
Sarah J. Caswell: The Francis Crick Institute
Simone Kunzelmann: The Francis Crick Institute
Laurence H. Arnold: The Francis Crick Institute
Andrew G. Purkiss: The Francis Crick Institute
Geoff Kelly: The Francis Crick Institute
Ian A. Taylor: The Francis Crick Institute

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract SAMHD1 regulates cellular 2′-deoxynucleoside-5′-triphosphate (dNTP) homeostasis by catalysing the hydrolysis of dNTPs into 2′-deoxynucleosides and triphosphate. In CD4+ myeloid lineage and resting T-cells, SAMHD1 blocks HIV-1 and other viral infections by depletion of the dNTP pool to a level that cannot support replication. SAMHD1 mutations are associated with the autoimmune disease Aicardi–Goutières syndrome and hypermutated cancers. Furthermore, SAMHD1 sensitises cancer cells to nucleoside-analogue anti-cancer therapies and is linked with DNA repair and suppression of the interferon response to cytosolic nucleic acids. Nevertheless, despite its requirement in these processes, the fundamental mechanism of SAMHD1-catalysed dNTP hydrolysis remained unknown. Here, we present structural and enzymological data showing that SAMHD1 utilises an active site, bi-metallic iron-magnesium centre that positions a hydroxide nucleophile in-line with the Pα-O5′ bond to catalyse phosphoester bond hydrolysis. This precise molecular mechanism for SAMHD1 catalysis, reveals how SAMHD1 down-regulates cellular dNTP and modulates the efficacy of nucleoside-based anti-cancer and anti-viral therapies.

Date: 2020
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DOI: 10.1038/s41467-020-16983-2

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