Hg(II) Coordination in Human Thioredoxin Reductase 1: Molecular Insights into Mercury Toxicity
11 affiliations
- 1Department of Geological Sciences, University of Saskatchewan, 114 Science Place, Saskatoon, Saskatchewan, Canada, S7N 5E2
- 2Canadian Light Source, University of Saskatchewan, 44 Innovation Blvd, Saskatoon, Saskatchewan, Canada, S7N 2V3
- 3Stanford Synchrotron Radiation Lightsource
- 4Stanford University
- 5Department of Medical Biochemistry and Biophysics (MBB
- 6Karolinska Institutet
- 7Department of Selenoprotein Research and the National Tumor Biology Laboratory
- 8National Institute of Oncology
- 9Toxicology Centre
- 10University of Saskatchewan
- 11Department of Chemistry
Abstract
Thioredoxin reductase 1 (TrxR1) is an essential selenoprotein oxidoreductase and a sensitive molecular target of mercury, but the coordination chemistry underlying its inhibition by inorganic Hg(II) remains unknown. We use complementary Hg LIII-edge and Se K-edge X-ray absorption spectroscopy (XAS), high-energy-resolution fluorescence-detected XAS (HERFDXAS), and density functional theory (DFT) to determine the Hg(II) coordination environment in inhibited human TrxR1. Se K-edge EXAFS provides direct evidence for Hg(II) coordination to catalytic Sec498 in wild-type TrxR1, with a Se–Hg distance of 2.44 Å. Hg LIII-edge EXAFS indicates predominantly two-coordinate, near-digonal Se–Hg–S coordination, with Hg–Se and Hg–S distances of 2.43 and 2.37 Å, respectively. Replacement of Sec498 by cysteine or serine gives bis-thiolate Hg(SR)2 coordination, demonstrating that Sec498 is not essential for Hg(II) binding. Hg Lα1 HERFD-XAS independently supports two-coordinate Hg(II) and distinguishes mixed sulfur/selenium coordination in wild-type TrxR1 from the bis-thiolate U498C variant. DFT calculations show that coordination by the adjacent C-terminal Cys497/Sec498 pair and structures involving the N-terminal redox center are compatible with spectroscopy, but do not unambiguously distinguish their relative energies. In contrast, bis-thiolate coordination in U498S, which retains only Cys497 at the C-terminal redox center, supports recruitment of a cysteine from the N-terminal site. These results directly characterize inorganic Hg(II) binding to TrxR1 and demonstrate how the strong, adaptable chalcogen coordination chemistry of Hg(II) enables it to target the catalytic machinery of this essential cellular redox enzyme.
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BibTeX
@misc{rengifo2026hgii,
title = {{Hg(II) Coordination in Human Thioredoxin Reductase 1: Molecular Insights into Mercury Toxicity}},
author = {Emerita Mendoza Rengifo and Clinton J. Kidman and Linda I. Vogt and Julien J. H. Cotelesage and Thomas Kroll and Dimosthenis Sokaras and Qing Cheng and Elias S. J. Arnér and Graham N. George and Ingrid J. Pickering},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010446/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010446/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Hg(II) Coordination in Human Thioredoxin Reductase 1: Molecular Insights into Mercury Toxicity
AU - Emerita Mendoza Rengifo
AU - Clinton J. Kidman
AU - Linda I. Vogt
AU - Julien J. H. Cotelesage
AU - Thomas Kroll
AU - Dimosthenis Sokaras
AU - Qing Cheng
AU - Elias S. J. Arnér
AU - Graham N. George
AU - Ingrid J. Pickering
PY - 2026
DA - 2026/10/14
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010446/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010446/v1
AB - Thioredoxin reductase 1 (TrxR1) is an essential selenoprotein oxidoreductase and a sensitive molecular target of mercury, but the coordination chemistry underlying its inhibition by inorganic Hg(II) remains unknown. We use complementary Hg LIII-edge and Se K-edge X-ray absorption spectroscopy (XAS), high-energy-resolution fluorescence-detected XAS (HERFDXAS), and density functional theory (DFT) to determine the Hg(II) coordination environment in inhibited human TrxR1. Se K-edge EXAFS provides direct evidence for Hg(II) coordination to catalytic Sec498 in wild-type TrxR1, with a Se–Hg distance of 2.44 Å. Hg LIII-edge EXAFS indicates predominantly two-coordinate, near-digonal Se–Hg–S coordination, with Hg–Se and Hg–S distances of 2.43 and 2.37 Å, respectively. Replacement of Sec498 by cysteine or serine gives bis-thiolate Hg(SR)2 coordination, demonstrating that Sec498 is not essential for Hg(II) binding. Hg Lα1 HERFD-XAS independently supports two-coordinate Hg(II) and distinguishes mixed sulfur/selenium coordination in wild-type TrxR1 from the bis-thiolate U498C variant. DFT calculations show that coordination by the adjacent C-terminal Cys497/Sec498 pair and structures involving the N-terminal redox center are compatible with spectroscopy, but do not unambiguously distinguish their relative energies. In contrast, bis-thiolate coordination in U498S, which retains only Cys497 at the C-terminal redox center, supports recruitment of a cysteine from the N-terminal site. These results directly characterize inorganic Hg(II) binding to TrxR1 and demonstrate how the strong, adaptable chalcogen coordination chemistry of Hg(II) enables it to target the catalytic machinery of this essential cellular redox enzyme.
ER -