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Title: Structural basis for the DASS/SLC13 family’s carboxylate transport, chemical inhibition, and pathogenesis



Citrate, α-ketoglutarate, and succinate are TCA cycle intermediates that also play essential roles in metabolic signalling and cellular regulation. These molecules are imported across the plasma membrane by the divalent anion sodium symporter (DASS) family, encoded by the SLC13 genes in humans. Underlining their biomedical importance, mutations in NaDC3 (SLC13A3) and NaCT (SLC13A5) result in neurological disorders. We determined several structures of two bacterial DASS proteins, including the previously unseen outward-facing state, to provide biophysical descriptions of the family's elevator transport mechanism and strict substrate coupling. Building from this, we determined the human NaCT structure in complexes with citrate or a small-molecule inhibitor. These structures reveal how the inhibitor arrests the transport cycle of NaCT, and explains compound selectivity. Together, the bacterial and NaCT structures provide a framework for understanding how various mutations abolish the transport activity of NaCT in the brain and thereby cause SLC13A5-epilepsy.


More information about David and his work can be found at those two links.

The seminar will be delivered via zoom.