小柯机器人

美国纽约大学医学院Da-Neng Wang等研究人员合作解析人源柠檬酸转运蛋白NaCT的结构及抑制机制。相关论文于2021年2月17日在线发表在《自然》杂志上。

肝细胞通过钠依赖的柠檬酸转运蛋白NaCT（由SLC13A5编码）来获取柠檬酸，因此，该蛋白是抗肥胖药物的潜在靶点。为了了解其抑制机制的结构基础，研究人员解析了人源NaCT与柠檬酸或小分子抑制剂结合的冷冻电镜结构。

这些结构揭示了抑制剂（与柠檬酸盐结合在同一位点）如何阻止NaCT的运输循环。NaCT抑制剂结构也解释了为什么该化合物相比于两种同源的人类二羧酸盐转运蛋白更能选择性地抑制NaCT，并提出了进一步改善亲和力和选择性的方法。最后，NaCT结构提供了一个框架，可用于了解各种突变如何消除NaCT在大脑中的运输活性，从而导致与新生儿SLC13A5突变相关的癫痫病（称为SLC13A5-癫痫病）。

据了解，柠檬酸是细胞三羧酸循环的中间产物。除了在能量代谢中起重要作用外，三羧酸阴离子还作为脂肪酸合成的前体和调节因子。因此，脂肪酸合成速率与柠檬酸的胞浆浓度直接相关。

附：英文原文

Title: Structure and inhibition mechanism of the human citrate transporter NaCT

Author: David B. Sauer, Jinmei Song, Bing Wang, Jacob K. Hilton, Nathan K. Karpowich, Joseph A. Mindell, William J. Rice, Da-Neng Wang

Issue&Volume: 2021-02-17

Abstract: Citrate 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 synthesis1,2,3. Thus, the rate of fatty acid synthesis correlates directly with the cytosolic concentration of citrate4,5. 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)6,7,8.

DOI: 10.1038/s41586-021-03230-x

Source: https://www.nature.com/articles/s41586-021-03230-x

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