| Structural highlights
8uvd is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Method: | Electron Microscopy, Resolution 2.16Å |
| Ligands: | 3PE, C14, CLR, NA, XKC |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Disease
S13A3_HUMAN The disease is caused by variants affecting the gene represented in this entry.
Function
S13A3_HUMAN High-affinity sodium-dicarboxylate cotransporter that accepts a range of substrates with 4-6 carbon atoms, such as the citric acid cycle intermediates succinate and alpha-ketoglutarate (2-oxoglutarate), as well as other compounds including N-acetyl-L-aspartate (PubMed:10794676, PubMed:10992006, PubMed:15561973, PubMed:17356845, PubMed:17426067, PubMed:24247155, PubMed:30635937). Transports the dicarboxylate into the cell with a probable stoichiometry of 3 Na(+) for 1 divalent dicarboxylate, rendering the process electrogenic (PubMed:10794676, PubMed:10992006). Can transport citrate in a Na(+)-dependent manner, recognizing the divalent form of citrate rather than the trivalent form which is normally found in blood (PubMed:10794676).[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
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(o), outward-occluded C(oo) and inward-open C(i). A dicarboxylate is first bound and recognized in C(o) and how the substrate interacts with NaDC3 in C(oo) likely helps to further determine the substrate specificity. A phenylalanine from the scaffold domain interacts with the bound dicarboxylate in the C(oo) 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.
Substrate translocation and inhibition in human dicarboxylate transporter NaDC3.,Li Y, Song J, Mikusevic V, Marden JJ, Becerril A, Kuang H, Wang B, Rice WJ, Mindell JA, Wang DN Nat Struct Mol Biol. 2024 Dec 2. doi: 10.1038/s41594-024-01433-0. PMID:39622972[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wang H, Fei YJ, Kekuda R, Yang-Feng TL, Devoe LD, Leibach FH, Prasad PD, Ganapathy V. Structure, function, and genomic organization of human Na(+)-dependent high-affinity dicarboxylate transporter. Am J Physiol Cell Physiol. 2000 May;278(5):C1019-30. PMID:10794676 doi:10.1152/ajpcell.2000.278.5.C1019
- ↑ Huang W, Wang H, Kekuda R, Fei YJ, Friedrich A, Wang J, Conway SJ, Cameron RS, Leibach FH, Ganapathy V. Transport of N-acetylaspartate by the Na(+)-dependent high-affinity dicarboxylate transporter NaDC3 and its relevance to the expression of the transporter in the brain. J Pharmacol Exp Ther. 2000 Oct;295(1):392-403 PMID:10992006
- ↑ Burckhardt BC, Lorenz J, Kobbe C, Burckhardt G. Substrate specificity of the human renal sodium dicarboxylate cotransporter, hNaDC-3, under voltage-clamp conditions. Am J Physiol Renal Physiol. 2005 Apr;288(4):F792-9. PMID:15561973 doi:10.1152/ajprenal.00360.2004
- ↑ Stellmer F, Keyser B, Burckhardt BC, Koepsell H, Streichert T, Glatzel M, Jabs S, Thiem J, Herdering W, Koeller DM, Goodman SI, Lukacs Z, Ullrich K, Burckhardt G, Braulke T, Mühlhausen C. 3-Hydroxyglutaric acid is transported via the sodium-dependent dicarboxylate transporter NaDC3. J Mol Med (Berl). 2007 Jul;85(7):763-70. PMID:17356845 doi:10.1007/s00109-007-0174-5
- ↑ Bai XY, Chen X, Sun AQ, Feng Z, Hou K, Fu B. Membrane topology structure of human high-affinity, sodium-dependent dicarboxylate transporter. FASEB J. 2007 Aug;21(10):2409-17. PMID:17426067 doi:10.1096/fj.06-7652com
- ↑ Schorbach L, Krick W, Burckhardt G, Burckhardt BC. Glutathione is a low-affinity substrate of the human sodium-dependent dicarboxylate transporter. Nephron Physiol. 2013;124(1-2):1-5. PMID:24247155 doi:10.1159/000356419
- ↑ Dewulf JP, Wiame E, Dorboz I, Elmaleh-Bergès M, Imbard A, Dumitriu D, Rak M, Bourillon A, Helaers R, Malla A, Renaldo F, Boespflug-Tanguy O, Vincent MF, Benoist JF, Wevers RA, Schlessinger A, Van Schaftingen E, Nassogne MC, Schiff M. SLC13A3 variants cause acute reversible leukoencephalopathy and α-ketoglutarate accumulation. Ann Neurol. 2019 Mar;85(3):385-395. PMID:30635937 doi:10.1002/ana.25412
- ↑ Li Y, Song J, Mikusevic V, Marden JJ, Becerril A, Kuang H, Wang B, Rice WJ, Mindell JA, Wang DN. Substrate translocation and inhibition in human dicarboxylate transporter NaDC3. Nat Struct Mol Biol. 2024 Dec 2. PMID:39622972 doi:10.1038/s41594-024-01433-0
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