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Structure paper

タイトル	Structure and inhibition mechanism of the human citrate transporter NaCT.
ジャーナル・号・ページ	Nature, Vol. 591, Issue 7848, Page 157-161, Year 2021
掲載日	2021年2月17日
著者	David B Sauer / Jinmei Song / Bing Wang / Jacob K Hilton / Nathan K Karpowich / Joseph A Mindell / William J Rice / Da-Neng Wang /
PubMed 要旨	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 ...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 synthesis. Thus, the rate of fatty acid synthesis correlates directly with the cytosolic concentration of citrate. 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).
リンク	Nature / PubMed:33597751 / PubMed Central
手法	EM (単粒子)
解像度	3.04 - 3.12 Å
構造データ	22456 7jsj EMDB-22456, PDB-7jsj: Structure of the NaCT-PF2 complex 手法: EM (単粒子) / 解像度: 3.12 Å 22457 7jsk EMDB-22457, PDB-7jsk: Structure of the NaCT-Citrate complex 手法: EM (単粒子) / 解像度: 3.04 Å
化合物	ChemComp-NAG: 2-acetamido-2-deoxy-beta-D-glucopyranose / N-アセチル-β-D-グルコサミン / N-アセチルグルコサミン ChemComp-X3M: (2R)-2-[2-(4-tert-butylphenyl)ethyl]-2-hydroxybutanedioic acid ChemComp-NA: Unknown entry / ナトリウムカチオン ChemComp-CIT: CITRIC ACID / クエン酸 / クエン酸
由来	homo sapiens (ヒト)
キーワード	MEMBRANE PROTEIN (膜タンパク質) / Transporter (運搬体タンパク質) / Inhibitor