Structure and inhibition mechanism of the human citrate transporter NaCT
| Autor: | William J. Rice, Joseph A. Mindell, Jacob K. Hilton, David B. Sauer, Jinmei Song, Nathan K. Karpowich, Bing Wang, Da-Neng Wang |
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| Rok vydání: | 2021 |
| Předmět: |
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Molecular 0301 basic medicine Malates medicine.disease_cause Tricarboxylate Citric Acid Article Substrate Specificity 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Humans Binding site Fatty acid synthesis Dicarboxylic Acid Transporters chemistry.chemical_classification Mutation Binding Sites Epilepsy Multidisciplinary Symporters Cryoelectron Microscopy Sodium Brain Fatty acid Transporter Phenylbutyrates Citric acid cycle Cytosol 030104 developmental biology chemistry Biochemistry Protein Multimerization Carrier Proteins 030217 neurology & neurosurgery |
| Zdroj: | Nature |
| ISSN: | 1476-4687 0028-0836 |
| Popis: | 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 synthesis1-3. 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)6-8. |
| Databáze: | OpenAIRE |
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