Engineering and Physical Sciences Research Council
EP/L000253/1
United Kingdom
Wellcome Trust
209194
United Kingdom
Wellcome Trust
100298
United Kingdom
Wellcome Trust
219531
United Kingdom
Wellcome Trust
215519
United Kingdom
Wellcome Trust
219531
United Kingdom
Medical Research Council (MRC, United Kingdom)
MR/M011984/1
United Kingdom
Medical Research Council (MRC, United Kingdom)
MR/S021043/1
United Kingdom
Citation
Journal: Nat Commun / Year: 2021 Title: Molecular basis for redox control by the human cystine/glutamate antiporter system xc. Authors: Joanne L Parker / Justin C Deme / Dimitrios Kolokouris / Gabriel Kuteyi / Philip C Biggin / Susan M Lea / Simon Newstead / Abstract: Cysteine plays an essential role in cellular redox homoeostasis as a key constituent of the tripeptide glutathione (GSH). A rate limiting step in cellular GSH synthesis is the availability of ...Cysteine plays an essential role in cellular redox homoeostasis as a key constituent of the tripeptide glutathione (GSH). A rate limiting step in cellular GSH synthesis is the availability of cysteine. However, circulating cysteine exists in the blood as the oxidised di-peptide cystine, requiring specialised transport systems for its import into the cell. System xc is a dedicated cystine transporter, importing cystine in exchange for intracellular glutamate. To counteract elevated levels of reactive oxygen species in cancerous cells system xc is frequently upregulated, making it an attractive target for anticancer therapies. However, the molecular basis for ligand recognition remains elusive, hampering efforts to specifically target this transport system. Here we present the cryo-EM structure of system xc in both the apo and glutamate bound states. Structural comparisons reveal an allosteric mechanism for ligand discrimination, supported by molecular dynamics and cell-based assays, establishing a mechanism for cystine transport in human cells.
History
Deposition
Jul 28, 2021
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Header (metadata) release
Nov 17, 2021
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Map release
Nov 17, 2021
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Update
Feb 2, 2022
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Current status
Feb 2, 2022
Processing site: PDBe / Status: Released
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Structure visualization
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