Molecular Basis for Redox Control by the Human Cystine/Glutamate Antiporter
bioRxiv preprint doi: https://doi.org/10.1101/2021.08.09.455631; this version posted August 9, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. Molecular basis for redox control by the human cystine/glutamate antiporter System xc-. Joanne L. Parker1, *, #, Justin C. Deme2,3,4#, Dimitrios Kolokouris1, Gabriel Kuteyi1, Philip C. Biggin1, Susan M. Lea2,3,4 *, Simon Newstead1,5*. 1Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK; 2Dunn School of Pathology, University of Oxford, Oxford, OX1 3RE, 3 Central Oxford Structural Molecular Imaging Centre, University of Oxford, South Parks Road, Oxford, OX1 3RE, 4Center for Structural Biology, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA, 5The Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, OX1 3QU, UK. Cysteine plays an essential role in cellular redox homeostasis 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.
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