8uvb
Structure of NaCT-PF4a complex
Structural highlights
DiseaseS13A5_HUMAN Undetermined early-onset epileptic encephalopathy;Amelocerebrohypohidrotic syndrome;Pyridoxine-dependent epilepsy. The disease is caused by variants affecting the gene represented in this entry. FunctionS13A5_HUMAN High-affinity sodium/citrate cotransporter that mediates citrate entry into cells. The transport process is electrogenic; it is the trivalent form of citrate rather than the divalent form that is recognized as a substrate. May facilitate the utilization of circulating citrate for the generation of metabolic energy and for the synthesis of fatty acids and cholesterol.[1] [2] 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[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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