1H6V

Mammalian thioredoxin reductase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.226 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Three-Dimensional Structure of a Mammalian Thioredoxin Reductase: Implication for Mechanism and Evolution of a Selenocysteine Dependent Enzyme

Sandalova, T.Zhong, L.Lindqvist, Y.Holmgren, A.Schneider, G.

(2001) Proc Natl Acad Sci U S A 98: 9533

  • DOI: https://doi.org/10.1073/pnas.171178698
  • Primary Citation of Related Structures:  
    1H6V

  • PubMed Abstract: 

    Thioredoxin reductases (TrxRs) from mammalian cells contain an essential selenocysteine residue in the conserved C-terminal sequence Gly-Cys-SeCys-Gly forming a selenenylsulfide in the oxidized enzyme. Reduction by NADPH generates a selenolthiol, which is the active site in reduction of Trx. The three-dimensional structure of the SeCys498Cys mutant of rat TrxR in complex with NADP(+) has been determined to 3.0-A resolution by x-ray crystallography. The overall structure is similar to that of glutathione reductase (GR), including conserved amino acid residues binding the cofactors FAD and NADPH. Surprisingly, all residues directly interacting with the substrate glutathione disulfide in GR are conserved despite the failure of glutathione disulfide to act as a substrate for TrxR. The 16-residue C-terminal tail, which is unique to mammalian TrxR, folds in such a way that it can approach the active site disulfide of the other subunit in the dimer. A model of the complex of TrxR with Trx suggests that electron transfer from NADPH to the disulfide of the substrate is possible without large conformational changes. The C-terminal extension typical of mammalian TrxRs has two functions: (i) it extends the electron transport chain from the catalytic disulfide to the enzyme surface, where it can react with Trx, and (ii) it prevents the enzyme from acting as a GR by blocking the redox-active disulfide. Our results suggest that mammalian TrxR evolved from the GR scaffold rather than from its prokaryotic counterpart. This evolutionary switch renders cell growth dependent on selenium.


  • Organizational Affiliation

    Division of Molecular Structural Biology and Medical Nobel Institute for Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden.


Macromolecules
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Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
THIOREDOXIN REDUCTASE
A, B, C, D, E
A, B, C, D, E, F
499Rattus norvegicusMutation(s): 1 
EC: 1.6.4.5
UniProt
Find proteins for O89049 (Rattus norvegicus)
Explore O89049 
Go to UniProtKB:  O89049
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO89049
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FAD
Query on FAD

Download Ideal Coordinates CCD File 
G [auth A]
I [auth B]
K [auth C]
M [auth D]
O [auth E]
G [auth A],
I [auth B],
K [auth C],
M [auth D],
O [auth E],
Q [auth F]
FLAVIN-ADENINE DINUCLEOTIDE
C27 H33 N9 O15 P2
VWWQXMAJTJZDQX-UYBVJOGSSA-N
NDP
Query on NDP

Download Ideal Coordinates CCD File 
H [auth A]
J [auth B]
L [auth C]
N [auth D]
P [auth E]
H [auth A],
J [auth B],
L [auth C],
N [auth D],
P [auth E],
R [auth F]
NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H30 N7 O17 P3
ACFIXJIJDZMPPO-NNYOXOHSSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.226 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.92α = 90
b = 140.464β = 94.64
c = 170.832γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
DENZOdata reduction
SCALEPACKdata scaling
EPMRphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2001-08-14
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2018-01-17
    Changes: Data collection
  • Version 1.4: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description