|Entry||Database: PDB / ID: 7jsj|
|Title||Structure of the NaCT-PF2 complex|
|Components||Solute carrier family 13 member 5|
|Keywords||MEMBRANE PROTEIN / Transporter / Inhibitor|
|Function / homology|
Function and homology information
citrate transmembrane transporter activity / citrate transport / sodium:dicarboxylate symporter activity / succinate transmembrane transporter activity / anion transmembrane transport / integral component of membrane / nucleoplasm / plasma membrane / cytosol
Sodium/sulphate symporter, conserved site / Solute carrier family 13
Solute carrier family 13 member 5
|Biological species||Homo sapiens (human)|
|Method||ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.12 Å|
|Authors||Sauer, D.B. / Wang, B. / Song, J. / Rice, W.J. / Wang, D.N.|
|Funding support|| United States, 7items |
|Citation||Journal: 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).
SummaryFull reportAbout validation report
|Structure viewer||Molecule: |
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A: Solute carrier family 13 member 5
B: Solute carrier family 13 member 5
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
Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C8H15NO6
Mass: 294.343 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H22O5 / Feature type: SUBJECT OF INVESTIGATION
|Has ligand of interest||Y|
|Experiment||Method: ELECTRON MICROSCOPY|
|EM experiment||Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction|
|Component||Name: Dimer of NaCT in complex with PF2 / Type: ORGANELLE OR CELLULAR COMPONENT / Entity ID: #1 / Source: RECOMBINANT|
|Molecular weight||Value: 0.125 MDa / Experimental value: YES|
|Source (natural)||Organism: Homo sapiens (human)|
|Source (recombinant)||Organism: Trichoplusia ni (cabbage looper)|
|Buffer solution||pH: 7.5|
|Specimen||Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES|
|Vitrification||Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K|
-Electron microscopy imaging
Model: Titan Krios / Image courtesy: FEI Company
|Microscopy||Model: FEI TITAN KRIOS|
|Electron gun||Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM|
|Electron lens||Mode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 22500 X / Nominal defocus max: 2300 nm / Nominal defocus min: 1300 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm|
|Image recording||Average exposure time: 10 sec. / Electron dose: 69.42 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)|
|Software||Name: PHENIX / Version: 1.18_3855: / Classification: refinement|
|CTF correction||Type: PHASE FLIPPING AND AMPLITUDE CORRECTION|
|Symmetry||Point symmetry: C1 (asymmetric)|
|3D reconstruction||Resolution: 3.12 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 600496 / Symmetry type: POINT|
|Refine LS restraints|
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