Da-Neng Wang, Professor, Department of Cell Biology, NYU Langone Medical Center, will give a seminar on "Structure and inhibition mechanism of the human liver citrate transporter NaCT"

ABSTRACT

Citrate is most well-known as an intermediate in the TCA 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. Thus, the rate of fatty acid synthesis correlates directly with the cytosolic citrate concentration. Liver cells import citrate via the sodium-dependent citrate transporter NaCT (SLC13A5), and as a consequence this protein is a potential target for anti-obesity drugs. To understand the structural basis of its inhibition mechanism, we have determined cryo-electron microscopy structures of human NaCT in complex with citrate and with a small molecule inhibitor. These structures reveal how the inhibitor, bound at the same site as citrate, arrests the protein’s transport cycle. 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.