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TitleMolecular basis for redox control by the human cystine/glutamate antiporter system xc.
Journal, issue, pagesNat Commun, Vol. 12, Issue 1, Page 7147, Year 2021
Publish dateDec 8, 2021
AuthorsJoanne L Parker / Justin C Deme / Dimitrios Kolokouris / Gabriel Kuteyi / Philip C Biggin / Susan M Lea / Simon Newstead /
PubMed AbstractCysteine 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.
External linksNat Commun / PubMed:34880232 / PubMed Central
MethodsEM (single particle)
Resolution3.4 - 3.7 Å
Structure data

13266

7p9u

EMDB-13266, PDB-7p9u:
Cryo EM structure of System XC- in complex with glutamate
Method: EM (single particle) / Resolution: 3.7 Å

13267

7p9v

EMDB-13267, PDB-7p9v:
Cryo EM structure of System XC-
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-GLU:
GLUTAMIC ACID

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / transporter glutamate cystine

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