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- PDB-8uve: Structure of NaDC3-Succinate complex in Coo-Ci conformation -

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Basic information

Entry
Database: PDB / ID: 8uve
TitleStructure of NaDC3-Succinate complex in Coo-Ci conformation
ComponentsNa(+)/dicarboxylate cotransporter 3
KeywordsTRANSPORT PROTEIN / Na(+)/dicarboxylate cotransporter(NaDC3) / Solute carries / Elevator type alternating access / membrane protein
Function / homology
Function and homology information


dicarboxylic acid transmembrane transporter activity / dicarboxylic acid transport / high-affinity sodium:dicarboxylate symporter activity / citrate transmembrane transporter activity / citrate transport / sodium:dicarboxylate symporter activity / alpha-ketoglutarate transmembrane transporter activity / Sodium-coupled sulphate, di- and tri-carboxylate transporters / succinate transmembrane transport / succinate transmembrane transporter activity ...dicarboxylic acid transmembrane transporter activity / dicarboxylic acid transport / high-affinity sodium:dicarboxylate symporter activity / citrate transmembrane transporter activity / citrate transport / sodium:dicarboxylate symporter activity / alpha-ketoglutarate transmembrane transporter activity / Sodium-coupled sulphate, di- and tri-carboxylate transporters / succinate transmembrane transport / succinate transmembrane transporter activity / glutathione transmembrane transport / glutathione transmembrane transporter activity / lipid transport / transport across blood-brain barrier / basolateral plasma membrane / extracellular exosome / plasma membrane
Similarity search - Function
Sodium:sulfate symporter transmembrane region / Solute carrier family 13
Similarity search - Domain/homology
1,2-Distearoyl-sn-glycerophosphoethanolamine / TETRADECANE / CHOLESTEROL / SUCCINIC ACID / Na(+)/dicarboxylate cotransporter 3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsLi, Y. / Wang, D.N. / Mindell, J.A. / Rice, W.J. / Song, J. / Mikusevic, V. / Marden, J.J. / Becerril, A. / Kuang, H. / Wang, B.
Funding support United States, 4items
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 Diabetes and Digestive and Kidney Disease (NIH/NIDDK)R01DK135088 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)R01AI165782 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM121994 United States
CitationJournal: Nat Struct Mol Biol / Year: 2024
Title: Substrate translocation and inhibition in human dicarboxylate transporter NaDC3.
Authors: Yan Li / Jinmei Song / Vedrana Mikusevic / Jennifer J Marden / Alissa Becerril / Huihui Kuang / Bing Wang / William J Rice / Joseph A Mindell / Da-Neng Wang /
Abstract: The human high-affinity sodium-dicarboxylate cotransporter (NaDC3) imports various substrates into the cell as tricarboxylate acid cycle intermediates, lipid biosynthesis precursors and signaling ...The human high-affinity sodium-dicarboxylate cotransporter (NaDC3) imports various substrates into the cell as tricarboxylate acid cycle intermediates, lipid biosynthesis precursors and signaling molecules. Understanding the cellular signaling process and developing inhibitors require knowledge of the structural basis of the dicarboxylate specificity and inhibition mechanism of NaDC3. To this end, we determined the cryo-electron microscopy structures of NaDC3 in various dimers, revealing the protomer in three conformations: outward-open C, outward-occluded C and inward-open C. A dicarboxylate is first bound and recognized in C and how the substrate interacts with NaDC3 in C likely helps to further determine the substrate specificity. A phenylalanine from the scaffold domain interacts with the bound dicarboxylate in the C state and modulates the kinetic barrier to the transport domain movement. Structural comparison of an inhibitor-bound structure of NaDC3 to that of the sodium-dependent citrate transporter suggests ways for making an inhibitor that is specific for NaDC3.
History
DepositionNov 2, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 25, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
B: Na(+)/dicarboxylate cotransporter 3
A: Na(+)/dicarboxylate cotransporter 3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,30724
Polymers134,4722
Non-polymers6,83522
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Protein , 1 types, 2 molecules BA

#1: Protein Na(+)/dicarboxylate cotransporter 3


Mass: 67236.023 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Solute carrier family 13 member 3 / Source: (gene. exp.) Homo sapiens (human) / Gene: SLC13A3 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q8WWT9

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Non-polymers , 5 types, 22 molecules

#2: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#3: Chemical ChemComp-SIN / SUCCINIC ACID


Mass: 118.088 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C4H6O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-C14 / TETRADECANE


Mass: 198.388 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C14H30
#5: Chemical
ChemComp-CLR / CHOLESTEROL


Mass: 386.654 Da / Num. of mol.: 10 / Source method: obtained synthetically / Formula: C27H46O
#6: Chemical ChemComp-3PE / 1,2-Distearoyl-sn-glycerophosphoethanolamine / 3-SN-PHOSPHATIDYLETHANOLAMINE / 1,2-DIACYL-SN-GLYCERO-3-PHOSPHOETHANOLAMINE


Mass: 748.065 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C41H82NO8P / Comment: phospholipid*YM

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Details

Has ligand of interestY
Has protein modificationN

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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 NaDC3 in complex with succinate / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.134 MDaYES
210.063062 MDaNO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
125 mMTris (Hydroxymethyl) Aminomethane HydrochlorideTris-HCl1
2100 mMsodium chlorideNaCl1
320 mMsuccinatesuccinate1
40.02 %glyco-diosgeninGDN1
SpecimenConc.: 6.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportDetails: Hold 10s before glow discharge / Grid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281.15 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: 105000 X / Calibrated magnification: 105000 X / Nominal defocus max: 1600 nm / Nominal defocus min: 1200 nm / Calibrated defocus min: 800 nm / Calibrated defocus max: 3000 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Temperature (max): 80 K / Temperature (min): 80 K / Residual tilt: 0.05 mradians
Image recordingAverage exposure time: 1.8 sec. / Electron dose: 52.58 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 5179
Details: 5179 untilted images were collected in super resolution mode at 40 frames per micrograph
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 20 eV
Image scansSampling size: 5 µm / Width: 5760 / Height: 4092

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Processing

EM software
IDNameVersionCategory
1Warp1.0.9particle selection
2Topaz0.2.5aparticle selection
3Leginon3.5image acquisition
5cryoSPARC3.3.1CTF correction
8UCSF Chimera1.15model fitting
9Coot0.9.6model fitting
11PHENIX1.19.2model refinement
12cryoSPARC3.3.1initial Euler assignment
13cryoSPARC3.3.1final Euler assignment
14cryoSPARC3.3.1classification
15cryoSPARC3.3.13D reconstruction
Image processingDetails: The micrographs with an overall resolution worse than 5 angstrom were excluded
CTF correctionDetails: CTF amplitude correction was performed after particle polishing
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2932803 / Details: Particles were selected from 5040 untilted images
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 228347 / Algorithm: FOURIER SPACE / Num. of class averages: 1 / Symmetry type: POINT
Atomic model buildingB value: 68.84 / Protocol: OTHER / Space: REAL / Target criteria: cross-correlation coefficient
Details: Initial local fitting was done using Chimera and then coot was used for ajustment.
Atomic model buildingChain residue range: 1-602 / Details: The whole model was used as an initial model / Source name: AlphaFold / Type: in silico model

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