RT Journal Article SR Electronic T1 Molecular basis for redox control by the human cystine/glutamate antiporter System xc- JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.08.09.455631 DO 10.1101/2021.08.09.455631 A1 Joanne L. Parker A1 Justin C. Deme A1 Dimitrios Kolokouris A1 Gabriel Kuteyi A1 Philip C. Biggin A1 Susan M. Lea A1 Simon Newstead YR 2021 UL http://biorxiv.org/content/early/2021/08/09/2021.08.09.455631.abstract AB 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. 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.Competing Interest StatementThe authors have declared no competing interest.