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From Proteopedia
Structure of NaDC3-Succinate complex in Coo-Ci conformation
Structural highlights
DiseaseS13A3_HUMAN The disease is caused by variants affecting the gene represented in this entry. FunctionS13A3_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 PubMedThe 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
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Categories: Homo sapiens | Large Structures | Becerril A | Kuang H | Li Y | Marden JJ | Mikusevic V | Mindell JA | Rice WJ | Song J | Wang B | Wang DN
