3B6P

Structure of TREX1 in complex with a nucleotide and inhibitor ions (sodium and zinc)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.285 
  • R-Value Work: 0.246 
  • R-Value Observed: 0.248 

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Literature

Structural and biochemical studies of TREX1 inhibition by metals. Identification of a new active histidine conserved in DEDDh exonucleases.

Brucet, M.Querol-Audi, J.Bertlik, K.Lloberas, J.Fita, I.Celada, A.

(2008) Protein Sci 17: 2059-2069

  • DOI: https://doi.org/10.1110/ps.036426.108
  • Primary Citation of Related Structures:  
    3B6O, 3B6P

  • PubMed Abstract: 

    TREX1 is the major exonuclease in mammalian cells, exhibiting the highest level of activity with a 3'-->5' activity. This exonuclease is responsible in humans for Aicardi-Goutières syndrome and for an autosomal dominant retinal vasculopathy with cerebral leukodystrophy. In addition, this enzyme is associated with systemic lupus erythematosus. TREX1 belongs to the exonuclease DEDDh family, whose members display low levels of sequence identity, while possessing a common fold and active site organization. For these exonucleases, a catalytic mechanism has been proposed that involves two divalent metal ions bound to the DEDD motif. Here we studied the interaction of TREX1 with the monovalent cations lithium and sodium. We demonstrate that these metals inhibit the exonucleolytic activity of TREX1, as measured by the classical gel method, as well as by a new technique developed for monitoring the real-time exonuclease reaction. The X-ray structures of the enzyme in complex with these two cations and with a nucleotide, a product of the exonuclease reaction, were determined at 2.1 A and 2.3 A, respectively. A comparison with the structures of the active complexes (in the presence of magnesium or manganese) explains that the inhibition mechanism is caused by the noncatalytic metals competing with distinct affinities for the two metal-binding sites and inducing subtle rearrangements in active centers. Our analysis also reveals that a histidine residue (His124), highly conserved in the DEDDh family, is involved in the activity of TREX1, as confirmed by mutational studies. Our results shed further light on the mechanism of activity of the DEDEh family of exonucleases.


  • Organizational Affiliation

    Macrophage Biology Group, Institute for Research in Biomedicine and University of Barcelona, Barcelona Science Park, 08028 Barcelona, Spain.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Three prime repair exonuclease 1
A, B, C, D
247Mus musculusMutation(s): 0 
Gene Names: Trex1
EC: 3.1.11.2
UniProt
Find proteins for Q91XB0 (Mus musculus)
Explore Q91XB0 
Go to UniProtKB:  Q91XB0
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ91XB0
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
TMP
Query on TMP

Download Ideal Coordinates CCD File 
G [auth A],
J [auth B],
M [auth C],
P [auth D]
THYMIDINE-5'-PHOSPHATE
C10 H15 N2 O8 P
GYOZYWVXFNDGLU-XLPZGREQSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
K [auth C],
N [auth D]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
F [auth A],
I [auth B],
L [auth C],
O [auth D]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.285 
  • R-Value Work: 0.246 
  • R-Value Observed: 0.248 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.772α = 90
b = 81.496β = 103.11
c = 92.539γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
ADSCdata collection
DENZOdata reduction
SCALEPACKdata scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2008-09-23
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-08-30
    Changes: Data collection, Database references, Derived calculations, Refinement description