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- PDB-7jsj: Structure of the NaCT-PF2 complex -

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Basic information

Entry
Database: PDB / ID: 7jsj
TitleStructure of the NaCT-PF2 complex
ComponentsSolute carrier family 13 member 5
KeywordsMEMBRANE PROTEIN / Transporter / Inhibitor
Function / homology
Function and homology information


oxaloacetate transport / organic acid:sodium symporter activity / fumarate transport / succinate transport / sodium:dicarboxylate symporter activity / citrate transmembrane transporter activity / citrate transport / Sodium-coupled sulphate, di- and tri-carboxylate transporters / alpha-ketoglutarate transport / succinate transmembrane transporter activity ...oxaloacetate transport / organic acid:sodium symporter activity / fumarate transport / succinate transport / sodium:dicarboxylate symporter activity / citrate transmembrane transporter activity / citrate transport / Sodium-coupled sulphate, di- and tri-carboxylate transporters / alpha-ketoglutarate transport / succinate transmembrane transporter activity / cellular response to lithium ion / transmembrane transport / nucleoplasm / identical protein binding / plasma membrane / cytosol
Similarity search - Function
Sodium/sulphate symporter, conserved site / Sodium:sulfate symporter family signature. / Sodium:sulfate symporter transmembrane region / Solute carrier family 13
Similarity search - Domain/homology
Chem-X3M / Na(+)/citrate cotransporter
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.12 Å
AuthorsSauer, D.B. / Wang, B. / Song, J. / Rice, W.J. / Wang, D.N.
Funding support United States, 7items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R01NS108151 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM121994 United States
American Cancer Society129844-PF-17-135-01-TBE United States
Department of Defense (DOD, United States)W81XWH-16-1-0153 United States
The G. Harold and Leila Y. Mathers Foundation United States
TESS Research Foundation United States
American Epilepsy Society United States
CitationJournal: Nature / Year: 2021
Title: Structure and inhibition mechanism of the human citrate transporter NaCT.
Authors: David B Sauer / Jinmei Song / Bing Wang / Jacob K Hilton / Nathan K Karpowich / Joseph A Mindell / William J Rice / Da-Neng Wang /
Abstract: Citrate is best known as an intermediate in the tricarboxylic acid cycle of the cell. In addition to this essential role in energy metabolism, the tricarboxylate anion also acts as both a precursor ...Citrate is best known as an intermediate in the tricarboxylic acid cycle of the cell. In addition to this essential role in energy metabolism, the tricarboxylate anion also acts as both a precursor and a regulator of fatty acid synthesis. Thus, the rate of fatty acid synthesis correlates directly with the cytosolic concentration of citrate. Liver cells import citrate through the sodium-dependent citrate transporter NaCT (encoded by SLC13A5) and, as a consequence, this protein is a potential target for anti-obesity drugs. Here, to understand the structural basis of its inhibition mechanism, we determined cryo-electron microscopy structures of human NaCT in complexes with citrate or a small-molecule inhibitor. These structures reveal how the inhibitor-which binds to the same site as citrate-arrests the transport cycle of NaCT. The NaCT-inhibitor structure also explains why the compound selectively inhibits NaCT over two homologous human dicarboxylate transporters, and suggests ways to further improve the affinity and selectivity. Finally, the NaCT structures provide a framework for understanding how various mutations abolish the transport activity of NaCT in the brain and thereby cause epilepsy associated with mutations in SLC13A5 in newborns (which is known as SLC13A5-epilepsy).
History
DepositionAug 14, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 24, 2021Provider: repository / Type: Initial release
Revision 1.1Mar 3, 2021Group: Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.identifier_ORCID
Revision 1.2Mar 10, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 23, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update / _pdbx_entry_details.has_protein_modification

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Structure visualization

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Assembly

Deposited unit
A: Solute carrier family 13 member 5
B: Solute carrier family 13 member 5
hetero molecules


Theoretical massNumber of molelcules
Total (without water)127,34510
Polymers126,2222
Non-polymers1,1238
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: light scattering
TypeNameSymmetry operationNumber
identity operation1_5551
Buried area5260 Å2
ΔGint-74 kcal/mol
Surface area37370 Å2

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Components

#1: Protein Solute carrier family 13 member 5 / Na(+)/citrate cotransporter / NaCT / Sodium-coupled citrate transporter / Sodium-dependent citrate transporter


Mass: 63110.812 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: SLC13A5, NACT / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q86YT5
#2: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#3: Chemical ChemComp-X3M / (2R)-2-[2-(4-tert-butylphenyl)ethyl]-2-hydroxybutanedioic acid


Mass: 294.343 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H22O5 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Na
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Dimer of NaCT in complex with PF2 / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.125 MDa / Experimental value: YES
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 22500 X / Nominal defocus max: 2300 nm / Nominal defocus min: 1300 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm
Image recordingAverage exposure time: 10 sec. / Electron dose: 69.42 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18_3855: / Classification: refinement
EM software
IDNameCategory
2Leginonimage acquisition
4WarpCTF correction
7Cootmodel fitting
9cryoSPARCinitial Euler assignment
10cryoSPARCfinal Euler assignment
11cryoSPARCclassification
12cryoSPARC3D reconstruction
19PHENIXmodel refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.12 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 600496 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0087576
ELECTRON MICROSCOPYf_angle_d1.07210336
ELECTRON MICROSCOPYf_dihedral_angle_d13.7912656
ELECTRON MICROSCOPYf_chiral_restr0.1811250
ELECTRON MICROSCOPYf_plane_restr0.0051236

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