Structural Basis for Oxidized Glutathione Recognition by Yeast Cadmium Factor 1
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| Title: | Structural Basis for Oxidized Glutathione Recognition by Yeast Cadmium Factor 1 |
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| Authors: | Tik Hang Soong, Clare F. Hotze, Darpan Raghav, Nitesh Kumar Khandelwal, Thomas M. Tomasiak |
| Publication Year: | 2025 |
| Subject Terms: | Biophysics, Biochemistry, Microbiology, Cell Biology, Genetics, Evolutionary Biology, Cancer, Computational Biology, Chemical Sciences not elsewhere classified, site works together, molecular dynamics simulations, including heavy metals, detoxifying electrophilic compounds, cellular survival assays, transports glutathione conjugated, glutathione binds tightly, different binding characteristics, transporting oxidized glutathione, oxidized glutathione recognition, 3 +, glutathione binding mode, drive substrate selectivity, oxidized diglutathione, recycle glutathione, complicated selectivity, substrate pocket, structural basis, safely sequester, major role, loose pocket |
| Description: | Transporters from the ABCC family have an essential role in detoxifying electrophilic compounds, including heavy metals and drugs, often after conjugation with glutathione. The Yeast Cadmium Factor 1 (Ycf1) transports glutathione conjugated to toxic heavy metals including Cd 2+ , Hg 2+ , and the metalloid As 3+ into the vacuole to safely sequester them in the cell. It also has a major role in transporting oxidized glutathione to help maintain redox balance and recycle glutathione. To understand the complicated selectivity and promiscuity of binding, we determined the cryo-EM structure of Ycf1 bound to the substrate, oxidized diglutathione. We identify a glutathione binding mode with different binding characteristics to each half of the glutathione. One half of glutathione binds tightly to the substrate pocket, and the other half bound in a loose pocket. We systematically measured binding determinants with cellular survival assays under high cadmium concentrations along with molecular dynamics simulations to show how each half of the site works together to drive substrate selectivity. |
| Document Type: | article in journal/newspaper |
| Language: | unknown |
| Relation: | https://figshare.com/articles/journal_contribution/Structural_Basis_for_Oxidized_Glutathione_Recognition_by_Yeast_Cadmium_Factor_1/29598177 |
| DOI: | 10.1021/jacs.4c16335.s002 |
| Availability: | https://doi.org/10.1021/jacs.4c16335.s002 https://figshare.com/articles/journal_contribution/Structural_Basis_for_Oxidized_Glutathione_Recognition_by_Yeast_Cadmium_Factor_1/29598177 |
| Rights: | CC BY-NC 4.0 |
| Accession Number: | edsbas.1ECAA4E2 |
| Database: | BASE |
Nájsť tento článok vo Web of Science | Abstract: | Transporters from the ABCC family have an essential role in detoxifying electrophilic compounds, including heavy metals and drugs, often after conjugation with glutathione. The Yeast Cadmium Factor 1 (Ycf1) transports glutathione conjugated to toxic heavy metals including Cd 2+ , Hg 2+ , and the metalloid As 3+ into the vacuole to safely sequester them in the cell. It also has a major role in transporting oxidized glutathione to help maintain redox balance and recycle glutathione. To understand the complicated selectivity and promiscuity of binding, we determined the cryo-EM structure of Ycf1 bound to the substrate, oxidized diglutathione. We identify a glutathione binding mode with different binding characteristics to each half of the glutathione. One half of glutathione binds tightly to the substrate pocket, and the other half bound in a loose pocket. We systematically measured binding determinants with cellular survival assays under high cadmium concentrations along with molecular dynamics simulations to show how each half of the site works together to drive substrate selectivity. |
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| DOI: | 10.1021/jacs.4c16335.s002 |