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

PDB id:

6txc

Name:

Hydrolase

Title:

Crystal structure of tetrameric human wt-samhd1 (residues 109-626) with gtp, datp, dcmpnpp and mg

Structure:

Deoxynucleoside triphosphate triphosphohydrolase samhd1. Chain: a, b, c, d, e, f, g, h, i, j, k, l, m, n, o, p. Synonym: dntpase,dendritic cell-derived ifng-induced protein,dcip, monocyte protein 5,mop-5,sam domain and hd domain-containing protein 1,hsamhd1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: samhd1, mop5. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: rosetta2

Resolution:

2.84Å R-factor: 0.229 R-free: 0.249

Authors:

E.R.Morris,S.Kunzelmann,S.J.Caswell,L.H.Arnold,A.Purkiss,G.Kelly, I.A.Taylor

Key ref:

E.R.Morris et al. (2020). Crystal structures of SAMHD1 inhibitor complexes reveal the mechanism of water-mediated dNTP hydrolysis. Nat Commun, 11, 3165. PubMed id: 32576829 DOI: 10.1038/s41467-020-16983-2

Date:

14-Jan-20 Release date: 24-Jun-20

Protein chains

Q9Y3Z3  (SAMH1_HUMAN) -  Deoxynucleoside triphosphate triphosphohydrolase SAMHD1 from Homo sapiens

Seq: 626 a.a.

Struc: 481 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.5.- - ?????

DOI no: 10.1038/s41467-020-16983-2

Nat Commun 11:3165 (2020)

PubMed id: 32576829

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

E.R.Morris, S.J.Caswell, S.Kunzelmann, L.H.Arnold, A.G.Purkiss, G.Kelly, I.A.Taylor.

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.