1H6V

Mammalian thioredoxin reductase

Summary for 1H6V

• Entry DOI: 10.2210/pdb1h6v/pdb
• Descriptor: THIOREDOXIN REDUCTASE, FLAVIN-ADENINE DINUCLEOTIDE, NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE, ... (4 entities in total)
• Functional Keywords: oxidoreductase, pyridine nucleotide-disulfide oxidoreductase, flavoprotein
• Biological source: RATTUS NORVEGICUS (RAT)
• Total number of polymer chains: 6
• Total formula weight: 337063.66

Authors

Sandalova, T.,Zhong, L.,Lindqvist, Y.,Holmgren, A.,Schneider, G. (deposition date: 2001-06-27, release date: 2001-08-14, Last modification date: 2024-10-16)

Primary citation

Sandalova, T.,Zhong, L.,Lindqvist, Y.,Holmgren, A.,Schneider, G.
Three-Dimensional Structure of a Mammalian Thioredoxin Reductase: Implication for Mechanism and Evolution of a Selenocysteine Dependent Enzyme
Proc.Natl.Acad.Sci.USA, 98:9533-, 2001

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.

PubMed: 11481439
DOI: 10.1073/PNAS.171178698

Experimental method

X-RAY DIFFRACTION (3 Å)