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  The structure of human thioredoxin reductase 1 provides insights into C-terminal rearrangements during catalysis

Fritz-Wolf, K., Urig, S., & Becker, K. (2007). The structure of human thioredoxin reductase 1 provides insights into C-terminal rearrangements during catalysis. Journal of Molecular Biology (London), 370(1), 116-127. doi:10.1016/j.jmb.2007.04.044.

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Genre: Journal Article
Alternative Title : The structure of human thioredoxin reductase 1 provides insights into C-terminal rearrangements during catalysis

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Fritz-Wolf, Karin1, Author              
Urig, Sabine, Author
Becker, Katja, Author
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1Department of Biomolecular Mechanisms, Max Planck Institute for Medical Research, Max Planck Society, ou_1497700              

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Free keywords: thioredoxin reductase 1; structure; inhibitor development; catalysis
 Abstract: Human thioredoxin reductase (hTrxR) is a homodimeric flavoprotein crucially involved in the regulation of cellular redox reactions, growth and differentiation. The enzyme contains a selenocysteine residue at its C-terminal active site that is essential for catalysis. This redox center is located on a flexible arm, solvent-exposed and reactive towards electrophilic inhibitors, thus representing a target for antitumor drug development. During catalysis reducing equivalents are transferred from the cofactor NADPH to FAD, then to the N-terminal active site cysteine residues and from there to the flexible C-terminal part of the other subunit to be finally delivered to a variety of second substrates at the molecule's surface. Here we report the first crystal structure of hTrxR1 (Sec→Cys) in complex with FAD and NADP+ at a resolution of 2.8 Å. From the crystals three different conformations of the carboxy-terminal arm could be deduced. The predicted movement of the arm is facilitated by the concerted action of the three side-chain residues of N418, N419 and W407, which act as a guiding bar for the C-terminal sliding process. As supported by previous kinetic data, the three visualized conformations might reflect different stages in enzymatic catalysis. Comparison with other disulfide reductases including human glutathione reductase revealed specific inhibitor binding sites in the intersubunit cavity of hTrxR that can be exploited for structure-based inhibitor development.

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Language(s): eng - English
 Dates: 2007-04-052007-01-042007-04-172007-04-242007-06-29
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Degree: -

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Title: Journal of Molecular Biology (London)
  Other : J Mol Biol
Source Genre: Journal
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Publ. Info: London : Academic Press
Pages: - Volume / Issue: 370 (1) Sequence Number: - Start / End Page: 116 - 127 Identifier: ISSN: 0022-2836
CoNE: https://pure.mpg.de/cone/journals/resource/954922646042