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- EMDB-13266: Cryo EM structure of System XC- in complex with glutamate -

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Basic information

Entry
Database: EMDB / ID: EMD-13266
TitleCryo EM structure of System XC- in complex with glutamate
Map datapostprocessed
Sample
  • Complex: System XC-
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
    • Protein or peptide: Cystine/glutamate transporter
  • Ligand: GLUTAMIC ACID
Function / homology
Function and homology information


cystine:glutamate antiporter activity / regulation of neutrophil apoptotic process / L-kynurenine transmembrane transport / L-kynurenine transmembrane transporter activity / regulation of cysteine metabolic process / regulation of glutathione biosynthetic process / regulation of glutamate metabolic process / regulation of melanin biosynthetic process / regulation of AMPA glutamate receptor clustering / L-cystine transport ...cystine:glutamate antiporter activity / regulation of neutrophil apoptotic process / L-kynurenine transmembrane transport / L-kynurenine transmembrane transporter activity / regulation of cysteine metabolic process / regulation of glutathione biosynthetic process / regulation of glutamate metabolic process / regulation of melanin biosynthetic process / regulation of AMPA glutamate receptor clustering / L-cystine transport / negative regulation of ferroptosis / neutral L-amino acid secondary active transmembrane transporter activity / Defective SLC7A7 causes lysinuric protein intolerance (LPI) / tyrosine transport / L-histidine transport / apical pole of neuron / dipeptide import across plasma membrane / aromatic amino acid transmembrane transporter activity / amino acid transport complex / L-amino acid transmembrane transporter activity / methionine transport / : / L-leucine import across plasma membrane / L-alanine transmembrane transporter activity / isoleucine transport / L-alanine import across plasma membrane / phenylalanine transport / valine transport / L-leucine transmembrane transporter activity / proline transport / amino acid transmembrane transport / regulation of protein transport / calcium:sodium antiporter activity / L-leucine transport / thyroid hormone transport / glutathione transmembrane transport / L-glutamate transmembrane transport / Amino acid transport across the plasma membrane / neutral L-amino acid transmembrane transporter activity / regulation of cellular response to oxidative stress / lens fiber cell differentiation / ventricular system development / intracellular glutamate homeostasis / L-glutamate import across plasma membrane / Tryptophan catabolism / astrocyte projection / striatum development / exogenous protein binding / amino acid transport / anchoring junction / Basigin interactions / limb development / response to redox state / microvillus membrane / NFE2L2 regulating anti-oxidant/detoxification enzymes / adult behavior / regulation of synapse organization / lung alveolus development / response to exogenous dsRNA / tryptophan transport / glutathione metabolic process / basal plasma membrane / response to nicotine / brush border membrane / modulation of chemical synaptic transmission / visual learning / response to organic cyclic compound / response to toxic substance / platelet aggregation / calcium ion transport / melanosome / double-stranded RNA binding / virus receptor activity / apical part of cell / cellular response to oxidative stress / regulation of cell population proliferation / basolateral plasma membrane / carbohydrate metabolic process / cadherin binding / symbiont entry into host cell / apical plasma membrane / protein heterodimerization activity / lysosomal membrane / synapse / cell surface / protein homodimerization activity / RNA binding / extracellular exosome / nucleoplasm / membrane / plasma membrane
Similarity search - Function
L-type amino acid transporter / Solute carrier family 3 member 2, N-terminal domain / 4F2 cell-surface antigen heavy chain / Solute carrier family 3 member 2 N-terminus / Amino acid/polyamine transporter I / Amino acid permease / Alpha amylase, catalytic domain / Glycosyl hydrolase, family 13, catalytic domain / Alpha-amylase domain / Glycosyl hydrolase, all-beta / Glycoside hydrolase superfamily
Similarity search - Domain/homology
Amino acid transporter heavy chain SLC3A2 / Cystine/glutamate transporter
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 Å
AuthorsParker JL / Deme JC / Lea SM / Newstead S
Funding support United Kingdom, 10 items
OrganizationGrant numberCountry
Wellcome Trust201536 United Kingdom
Wolfson FoundationWL160052 United Kingdom
Engineering and Physical Sciences Research CouncilEP/L000253/1 United Kingdom
Wellcome Trust209194 United Kingdom
Wellcome Trust100298 United Kingdom
Wellcome Trust219531 United Kingdom
Wellcome Trust215519 United Kingdom
Wellcome Trust219531 United Kingdom
Medical Research Council (MRC, United Kingdom)MR/M011984/1 United Kingdom
Medical Research Council (MRC, United Kingdom)MR/S021043/1 United Kingdom
CitationJournal: 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
DepositionJul 28, 2021-
Header (metadata) releaseNov 17, 2021-
Map releaseNov 17, 2021-
UpdateFeb 2, 2022-
Current statusFeb 2, 2022Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7p9u
  • Surface level: 0.3
  • Imaged by UCSF Chimera
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  • Simplified surface model + fitted atomic model
  • Atomic modelsPDB-7p9u
  • Imaged by Jmol
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_13266.png

Downloads & links

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Map

FileDownload / File: emd_13266.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Annotationpostprocessed
Voxel sizeX=Y=Z: 0.832 Å
Density
Contour LevelBy AUTHOR: 0.3 / Movie #1: 0.3
Minimum - Maximum-0.72325456 - 2.0716367
Average (Standard dev.)-0.0022032396 (±0.04088653)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.8320.8320.832
M x/y/z320320320
origin x/y/z0.0000.0000.000
length x/y/z266.240266.240266.240
α/β/γ90.00090.00090.000
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS320320320
D min/max/mean-0.7232.072-0.002

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Supplemental data

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Mask #1

Fileemd_13266_msk_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Additional map: #1

Fileemd_13266_additional_1.map
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Half map: #2

Fileemd_13266_half_map_1.map
Projections & Slices
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Histogram

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Half map: #1

Fileemd_13266_half_map_2.map
Projections & Slices
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Sample components

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Entire : System XC-

EntireName: System XC-
Components
  • Complex: System XC-
    • Protein or peptide: 4F2 cell-surface antigen heavy chain
    • Protein or peptide: Cystine/glutamate transporter
  • Ligand: GLUTAMIC ACID

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Supramolecule #1: System XC-

SupramoleculeName: System XC- / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2
Source (natural)Organism: Homo sapiens (human)
Recombinant expressionOrganism: Homo sapiens (human)

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Macromolecule #1: 4F2 cell-surface antigen heavy chain

MacromoleculeName: 4F2 cell-surface antigen heavy chain / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 69.161867 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MHHHHHHHHE LQPPEASIAV VSIPRQLPGS HSEAGVQGLS AGDDSELGSH CVAQTGLELL ASGDPLPSAS QNAEMIETGS DCVTQAGLQ LLASSDPPAL ASKNAEVTGT MSQDTEVDMK EVELNELEPE KQPMNAASGA AMSLAGAEKN GLVKIKVAED E AEAAAAAK ...String:
MHHHHHHHHE LQPPEASIAV VSIPRQLPGS HSEAGVQGLS AGDDSELGSH CVAQTGLELL ASGDPLPSAS QNAEMIETGS DCVTQAGLQ LLASSDPPAL ASKNAEVTGT MSQDTEVDMK EVELNELEPE KQPMNAASGA AMSLAGAEKN GLVKIKVAED E AEAAAAAK FTGLSKEELL KVAGSPGWVR TRWALLLLFW LGWLGMLAGA VVIIVRAPRC RELPAQKWWH TGALYRIGDL QA FQGHGAG NLAGLKGRLD YLSSLKVKGL VLGPIHKNQK DDVAQTDLLQ IDPNFGSKED FDSLLQSAKK KSIRVILDLT PNY RGENSW FSTQVDTVAT KVKDALEFWL QAGVDGFQVR DIENLKDASS FLAEWQNITK GFSEDRLLIA GTNSSDLQQI LSLL ESNKD LLLTSSYLSD SGSTGEHTKS LVTQYLNATG NRWCSWSLSQ ARLLTSFLPA QLLRLYQLML FTLPGTPVFS YGDEI GLDA AALPGQPMEA PVMLWDESSF PDIPGAVSAN MTVKGQSEDP GSLLSLFRRL SDQRSKERSL LHGDFHAFSA GPGLFS YIR HWDQNERFLV VLNFGDVGLS AGLQASDLPA SASLPAKADL LLSTQPGREE GSPLELERLK LEPHEGLLLR FPYAA

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Macromolecule #2: Cystine/glutamate transporter

MacromoleculeName: Cystine/glutamate transporter / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 56.466605 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MDYKDDDDKV RKPVVSTISK GGYLQGNVNG RLPSLGNKEP PGQEKVQLKR KVTLLRGVSI IIGTIIGAGI FISPKGVLQN TGSVGMSLT IWTVCGVLSL FGALSYAELG TTIKKSGGHY TYILEVFGPL PAFVRVWVEL LIIRPAATAV ISLAFGRYIL E PFFIQCEI ...String:
MDYKDDDDKV RKPVVSTISK GGYLQGNVNG RLPSLGNKEP PGQEKVQLKR KVTLLRGVSI IIGTIIGAGI FISPKGVLQN TGSVGMSLT IWTVCGVLSL FGALSYAELG TTIKKSGGHY TYILEVFGPL PAFVRVWVEL LIIRPAATAV ISLAFGRYIL E PFFIQCEI PELAIKLITA VGITVVMVLN SMSVSWSARI QIFLTFCKLT AILIIIVPGV MQLIKGQTQN FKDAFSGRDS SI TRLPLAF YYGMYAYAGW FYLNFVTEEV ENPEKTIPLA ICISMAIVTI GYVLTNVAYF TTINAEELLL SNAVAVTFSE RLL GNFSLA VPIFVALSCF GSMNGGVFAV SRLFYVASRE GHLPEILSMI HVRKHTPLPA VIVLHPLTMI MLFSGDLDSL LNFL SFARW LFIGLAVAGL IYLRYKCPDM HRPFKVPLFI PALFSFTCLF MVALSLYSDP FSTGIGFVIT LTGVPAYYLF IIWDK KPRW FRIMSEKITR TLQIILEVVP EEDKL

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Macromolecule #3: GLUTAMIC ACID

MacromoleculeName: GLUTAMIC ACID / type: ligand / ID: 3 / Number of copies: 1 / Formula: GLU
Molecular weightTheoretical: 147.129 Da
Chemical component information

ChemComp-GLU:
GLUTAMIC ACID / Glutamic acid

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 59.1 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 79698
FSC plot (resolution estimation)

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