PDBsum entry 6txc

Hydrolase

PDB id: 6txc

Contents

Protein chains

(+ 10 more) 481 a.a.

Ligands

0KX ×16

GTP ×16

SO4 ×9

DTP ×16

Metals

_FE ×16

_MG ×42

References listed in PDB file

Key reference

• Title: Crystal structures of samhd1 inhibitor complexes reveal the mechanism of water-Mediated dntp hydrolysis.
• Authors: E.R.Morris, S.J.Caswell, S.Kunzelmann, L.H.Arnold, A.G.Purkiss, G.Kelly, I.A.Taylor.
• Ref.: Nat Commun, 2020, 11, 3165. [DOI no: 10.1038/s41467-020-16983-2]
• PubMed id: 32576829

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.