PDBsum entry 5ao1

Hydrolase

PDB id: 5ao1

Contents

Protein chains

457 a.a.

Ligands

DG3 ×8

SO4 ×4

Metals

_MG ×4

_FE ×4

Waters ×170

PDB id:

5ao1

Name:

Hydrolase

Title:

Crystal structure of human samhd1 (amino acid residues 115-583) bound to ddgtp

Structure:

Deoxynucleoside triphosphate triphosphohydrolase samhd1. Chain: a, b, c, d. Fragment: unp residues 115-583. Synonym: dntpase, dendritic cell-derived ifng-induced protein, dcip, monocyte protein 5, mop-5, sam domain and hd domain-containing protein 1, samhd1. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: rosetta2.

Resolution:

2.55Å R-factor: 0.173 R-free: 0.220

Authors:

D.Schwefel,I.A.Taylor

Key ref:

L.H.Arnold et al. (2015). Phospho-dependent Regulation of SAMHD1 Oligomerisation Couples Catalysis and Restriction. Plos Pathog, 11, e1005194. PubMed id: 26431200 DOI: 10.1371/journal.ppat.1005194

Date:

09-Sep-15 Release date: 14-Oct-15

Protein chains

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

Seq: 626 a.a.

Struc: 457 a.a.

Enzyme reactions

• Enzyme class: E.C.3.1.5.- - ?????

DOI no: 10.1371/journal.ppat.1005194

Plos Pathog 11:e1005194 (2015)

PubMed id: 26431200

Phospho-dependent Regulation of SAMHD1 Oligomerisation Couples Catalysis and Restriction.

L.H.Arnold, H.C.Groom, S.Kunzelmann, D.Schwefel, S.J.Caswell, P.Ordonez, M.C.Mann, S.Rueschenbaum, D.C.Goldstone, S.Pennell, S.A.Howell, J.P.Stoye, M.Webb, I.A.Taylor, K.N.Bishop.

ABSTRACT

SAMHD1 restricts HIV-1 infection of myeloid-lineage and resting CD4+ T-cells. Most likely this occurs through deoxynucleoside triphosphate triphosphohydrolase activity that reduces cellular dNTP to a level where reverse transcriptase cannot function, although alternative mechanisms have been proposed recently. Here, we present combined structural and virological data demonstrating that in addition to allosteric activation and triphosphohydrolase activity, restriction correlates with the capacity of SAMHD1 to form "long-lived" enzymatically competent tetramers. Tetramer disruption invariably abolishes restriction but has varied effects on in vitro triphosphohydrolase activity. SAMHD1 phosphorylation also ablates restriction and tetramer formation but without affecting triphosphohydrolase steady-state kinetics. However phospho-SAMHD1 is unable to catalyse dNTP turnover under conditions of nucleotide depletion. Based on our findings we propose a model for phosphorylation-dependent regulation of SAMHD1 activity where dephosphorylation switches housekeeping SAMHD1 found in cycling cells to a high-activity stable tetrameric form that depletes and maintains low levels of dNTPs in differentiated cells.