7jsk | pdb_00007jsk
Structure of the NaCT-Citrate complex
Structural highlights
Disease[S13A5_HUMAN] Undetermined early-onset epileptic encephalopathy;Amelocerebrohypohidrotic syndrome;Pyridoxine-dependent epilepsy. The disease is caused by variants affecting the gene represented in this entry. Function[S13A5_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 PubMedCitrate 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(1-3). Thus, the rate of fatty acid synthesis correlates directly with the cytosolic concentration of citrate(4,5). 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)(6-8). Structure and inhibition mechanism of the human citrate transporter NaCT.,Sauer DB, Song J, Wang B, Hilton JK, Karpowich NK, Mindell JA, Rice WJ, Wang DN Nature. 2021 Feb 17. pii: 10.1038/s41586-021-03230-x. doi:, 10.1038/s41586-021-03230-x. PMID:33597751[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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