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

DOI: 10.1038/s41467-020-16983-2 DOI Help

Authors: Elizabeth R. Morris (The Francis Crick Institute (Midland Road)) , Sarah J. Caswell (The Francis Crick Institute (Midland Road)) , 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)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Nature Communications , VOL 11

State: Published (Approved)
Published: June 2020
Diamond Proposal Number(s): 13775 , 18566

Open Access Open Access

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.

Diamond Keywords: Human Immunodeficiency Virus (HIV); Viruses

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: Swiss Light Source

Added On: 24/06/2020 09:29

Documents:
s41467-020-16983-2.pdf

Discipline Tags:

Life Sciences & Biotech Health & Wellbeing Autoimmune Diseases Cancer Drug Discovery Infectious Diseases Non-Communicable Diseases Pathogens Structural biology

Technical Tags:

Diffraction Macromolecular Crystallography (MX)