Download MendeleyCrystal structures of SAMHD1 inhibitor complexes reveal the mechanism of water-mediated dNTP hydrolysis.
Morris, E.R., Caswell, S.J., Kunzelmann, S., Arnold, L.H., Purkiss, A.G., Kelly, G., Taylor, I.A.(2020) Nat Commun 11: 3165-3165
- PubMed: 32576829
- DOI: https://doi.org/10.1038/s41467-020-16983-2
- Primary Citation of Related Structures:
6TX0, 6TXA, 6TXC, 6TXE, 6TXF, 6XU1, 6YOM - PubMed 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 P α -O 5' 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.
Organizational Affiliation:
Macromolecular Structure Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.
