3qfa

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Crystal structure of the human thioredoxin reductase-thioredoxin complexCrystal structure of the human thioredoxin reductase-thioredoxin complex

Structural highlights

3qfa is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:,
Gene:GRIM12, KDRF, TXNRD1 (Homo sapiens), TRDX, TRX, TRX1, TXN (Homo sapiens)
Activity:Thioredoxin-disulfide reductase, with EC number 1.8.1.9
Resources:FirstGlance, OCA, RCSB, PDBsum

Function

[TRXR1_HUMAN] Isoform 1 may possess glutaredoxin activity as well as thioredoxin reductase activity and induces actin and tubulin polymerization, leading to formation of cell membrane protrusions. Isoform 4 enhances the transcriptional activity of estrogen receptors alpha and beta while isoform 5 enhances the transcriptional activity of the beta receptor only. Isoform 5 also mediates cell death induced by a combination of interferon-beta and retinoic acid.[1] [2] [3] [4] [THIO_HUMAN] Participates in various redox reactions through the reversible oxidation of its active center dithiol to a disulfide and catalyzes dithiol-disulfide exchange reactions. Plays a role in the reversible S-nitrosylation of cysteine residues in target proteins, and thereby contributes to the response to intracellular nitric oxide. Nitrosylates the active site Cys of CASP3 in response to nitric oxide (NO), and thereby inhibits caspase-3 activity. Induces the FOS/JUN AP-1 DNA-binding activity in ionizing radiation (IR) cells through its oxidation/reduction status and stimulates AP-1 transcriptional activity.[5] [6] [7] [8] [9] ADF augments the expression of the interleukin-2 receptor TAC (IL2R/P55).[10] [11] [12] [13] [14]

Publication Abstract from PubMed

Thioredoxin reductase 1 (TrxR1) is a homodimeric flavoprotein crucially involved in the regulation of cellular redox homeostasis, growth, and differentiation. Its importance in various diseases makes TrxR1 a highly interesting drug target. Here we present the first crystal structures of human TrxR1 in complex with its substrate thioredoxin (Trx). The carboxy-terminal redox centre is found about 20 A apart from the amino-terminal redox centre, with no major conformational changes in TrxR or Trx. Thus, our structure confirms that the enzyme uses a flexible C-terminal arm for electron transport to its substrates, which is stabilized by a guiding bar for controlled transfer. This notion is supported by mutational analyses. Furthermore, essential residues of the interface region were characterized both structurally and functionally. The structure provides templates for future drug design, and contributes to our understanding of redox regulatory processes in mammals.

Crystal structure of the human thioredoxin reductase-thioredoxin complex.,Fritz-Wolf K, Kehr S, Stumpf M, Rahlfs S, Becker K Nat Commun. 2011 Jul 12;2:383. doi: 10.1038/ncomms1382. PMID:21750537[15]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Hofmann ER, Boyanapalli M, Lindner DJ, Weihua X, Hassel BA, Jagus R, Gutierrez PL, Kalvakolanu DV. Thioredoxin reductase mediates cell death effects of the combination of beta interferon and retinoic acid. Mol Cell Biol. 1998 Nov;18(11):6493-504. PMID:9774665
  2. ↑ Tamura T, Stadtman TC. A new selenoprotein from human lung adenocarcinoma cells: purification, properties, and thioredoxin reductase activity. Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1006-11. PMID:8577704
  3. ↑ Damdimopoulos AE, Miranda-Vizuete A, Treuter E, Gustafsson JA, Spyrou G. An alternative splicing variant of the selenoprotein thioredoxin reductase is a modulator of estrogen signaling. J Biol Chem. 2004 Sep 10;279(37):38721-9. Epub 2004 Jun 14. PMID:15199063 doi:http://dx.doi.org/10.1074/jbc.M402753200
  4. ↑ Dammeyer P, Damdimopoulos AE, Nordman T, Jimenez A, Miranda-Vizuete A, Arner ES. Induction of cell membrane protrusions by the N-terminal glutaredoxin domain of a rare splice variant of human thioredoxin reductase 1. J Biol Chem. 2008 Feb 1;283(5):2814-21. Epub 2007 Nov 27. PMID:18042542 doi:http://dx.doi.org/10.1074/jbc.M708939200
  5. ↑ Jacquot JP, de Lamotte F, Fontecave M, Schurmann P, Decottignies P, Miginiac-Maslow M, Wollman E. Human thioredoxin reactivity-structure/function relationship. Biochem Biophys Res Commun. 1990 Dec 31;173(3):1375-81. PMID:2176490
  6. ↑ Hirota K, Matsui M, Iwata S, Nishiyama A, Mori K, Yodoi J. AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3633-8. PMID:9108029
  7. ↑ Wei SJ, Botero A, Hirota K, Bradbury CM, Markovina S, Laszlo A, Spitz DR, Goswami PC, Yodoi J, Gius D. Thioredoxin nuclear translocation and interaction with redox factor-1 activates the activator protein-1 transcription factor in response to ionizing radiation. Cancer Res. 2000 Dec 1;60(23):6688-95. PMID:11118054
  8. ↑ Mitchell DA, Marletta MA. Thioredoxin catalyzes the S-nitrosation of the caspase-3 active site cysteine. Nat Chem Biol. 2005 Aug;1(3):154-8. Epub 2005 Jul 10. PMID:16408020 doi:http://dx.doi.org/nchembio720
  9. ↑ Mitchell DA, Morton SU, Fernhoff NB, Marletta MA. Thioredoxin is required for S-nitrosation of procaspase-3 and the inhibition of apoptosis in Jurkat cells. Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11609-14. Epub 2007 Jul 2. PMID:17606900 doi:http://dx.doi.org/0704898104
  10. ↑ Jacquot JP, de Lamotte F, Fontecave M, Schurmann P, Decottignies P, Miginiac-Maslow M, Wollman E. Human thioredoxin reactivity-structure/function relationship. Biochem Biophys Res Commun. 1990 Dec 31;173(3):1375-81. PMID:2176490
  11. ↑ Hirota K, Matsui M, Iwata S, Nishiyama A, Mori K, Yodoi J. AP-1 transcriptional activity is regulated by a direct association between thioredoxin and Ref-1. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3633-8. PMID:9108029
  12. ↑ Wei SJ, Botero A, Hirota K, Bradbury CM, Markovina S, Laszlo A, Spitz DR, Goswami PC, Yodoi J, Gius D. Thioredoxin nuclear translocation and interaction with redox factor-1 activates the activator protein-1 transcription factor in response to ionizing radiation. Cancer Res. 2000 Dec 1;60(23):6688-95. PMID:11118054
  13. ↑ Mitchell DA, Marletta MA. Thioredoxin catalyzes the S-nitrosation of the caspase-3 active site cysteine. Nat Chem Biol. 2005 Aug;1(3):154-8. Epub 2005 Jul 10. PMID:16408020 doi:http://dx.doi.org/nchembio720
  14. ↑ Mitchell DA, Morton SU, Fernhoff NB, Marletta MA. Thioredoxin is required for S-nitrosation of procaspase-3 and the inhibition of apoptosis in Jurkat cells. Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11609-14. Epub 2007 Jul 2. PMID:17606900 doi:http://dx.doi.org/0704898104
  15. ↑ Fritz-Wolf K, Kehr S, Stumpf M, Rahlfs S, Becker K. Crystal structure of the human thioredoxin reductase-thioredoxin complex. Nat Commun. 2011 Jul 12;2:383. doi: 10.1038/ncomms1382. PMID:21750537 doi:10.1038/ncomms1382

3qfa, resolution 2.20Å

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